Tricyclic sulphonamide compounds and methods of making and using same

ABSTRACT

The invention provides tricyclic compounds and their use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making various tricyclic compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application61/722,449 filed Nov. 5, 2012, hereby incorporated by reference in itsentirety.

BACKGROUND

Over 1.1 billion people worldwide are reported to be overweight. Obesityis estimated to affect over 90 million people in the United Statesalone. Twenty-five percent of the population in the United States overthe age of twenty is considered clinically obese. While being overweightor obese presents problems (for example restriction of mobility,discomfort in tight spaces such as theater or airplane seats, socialdifficulties, etc.), these conditions, in particular clinical obesity,affect other aspects of health, i.e., diseases and other adverse healthconditions associated with, exacerbated by, or precipitated by beingoverweight or obese. The estimated mortality from obesity-relatedconditions in the United States is over 300,000 annually (O'Brien et al.Amer J Surgery (2002) 184:4S-8S; and Hill et al. (1998) Science,280:1371).

There is no curative treatment for being overweight or obese.Traditional pharmacotherapies for treating an overweight or obesesubject, such as serotonin and noradrenergic re-uptake inhibitors,noradrenergic re-uptake inhibitors, selective serotonin re-uptakeinhibitors, intestinal lipase inhibitors, or surgeries such as stomachstapling or gastric banding, have been shown to provide minimalshort-term benefits or significant rates of relapse, and have furthershown harmful side-effects to patients.

MetAP2 encodes a protein that functions at least in part byenzymatically removing the amino terminal methionine residue fromcertain newly translated proteins such as glyceraldehyde-3-phosphatedehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increasedexpression of the MetAP2 gene has been historically associated withvarious forms of cancer. Molecules inhibiting the enzymatic activity ofMetAP2 have been identified and have been explored for their utility inthe treatment of various tumor types (Wang et al. (2003) Cancer Res.63:7861) and infectious diseases such as microsporidiosis,leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34).Notably, inhibition of MetAP2 activity in obese and obese-diabeticanimals leads to a reduction in body weight in part by increasing theoxidation of fat and in part by reducing the consumption of food(Rupnick et al. (2002) Proc. Natl. Acad. Sci. USA 99:10730).

Such MetAP2 inhibitors may be useful as well for patients with excessadiposity and conditions related to adiposity including type 2 diabetes,hepatic steatosis, and cardiovascular disease (via e.g. amelioratinginsulin resistance, reducing hepatic lipid content, and reducing cardiacworkload). Accordingly, compounds capable of modulating MetAP2 areneeded to address the treatment of obesity and related diseases as wellas other ailments favorably responsive to MetAP2 modulator treatment.

SUMMARY

The invention provides, for example, compounds which may be modulatorsof MetAP2, and their use as medicinal agents, processes for theirpreparation, and pharmaceutical compositions containing them as anactive ingredient both alone or in combination with other agents, aswell as provides for their use as medicaments and/or in the manufactureof medicaments for the inhibition of MetAP2 activity in warm-bloodedanimals such as humans. In particular this invention relates tocompounds useful for the treatment of obesity, type 2 diabetes, andother obesity-associated conditions. Also provided are pharmaceuticalcompositions comprising at least one disclosed compound and apharmaceutically acceptable carrier.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Before further description of the presentinvention, certain terms employed in the specification, examples andappended claims are collected here. These definitions should be read inlight of the remainder of the disclosure and as understood by a personof skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

DEFINITIONS

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkylgroup attached to oxygen (alkyl-O—). Exemplary alkoxy groups include,but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms,referred to herein as C₁₋₆alkoxy, and C₂₋₆alkoxy, respectively.Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy,isopropoxy, etc.

The term “alkoxyalkyl” as used herein refers to a straight or branchedalkyl group attached to oxygen, attached to a second straight orbranched alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groupsinclude, but are not limited to, alkoxyalkyl groups in which each of thealkyl groups independently contains 1-6 carbon atoms, referred to hereinas C₁₋₆alkoxy-C₁₋₆alkyl. Exemplary alkoxyalkyl groups include, but arenot limited to methoxymethyl, 2-methoxyethyl, 1-methoxyethyl,2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl etc.

The term “alkyoxycarbonyl” as used herein refers to a straight orbranched alkyl group attached to oxygen, attached to a carbonyl group(alkyl-O—C(O)—). Exemplary alkoxycarbonyl groups include, but are notlimited to, alkoxycarbonyl groups of 1-6 carbon atoms, referred toherein as C₁₋₆alkoxycarbonyl. Exemplary alkoxycarbonyl groups include,but are not limited to, methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, etc.

The term “alkenyloxy” used herein refers to a straight or branchedalkenyl group attached to oxygen (alkenyl-O—). Exemplary alkenyloxygroups include, but are not limited to, groups with an alkenyl group of3-6 carbon atoms, referred to herein as C₃₋₆alkenyloxy. Exemplary“alkenyloxy” groups include, but are not limited to allyloxy,butenyloxy, etc.

The term “alkynyloxy” used herein refers to a straight or branchedalkynyl group attached to oxygen (alkynyl-O). Exemplary alkynyloxygroups include, but are not limited to, groups with an alkynyl group of3-6 carbon atoms, referred to herein as C₃₋₆alkynyloxy. Exemplaryalkynyloxy groups include, but are not limited to, propynyloxy,butynyloxy, etc.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon. Exemplary alkyl groups include, but are notlimited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbonatoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, and C₁₋₃alkyl,respectively. Exemplary alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

The term “alkylcarbonyl” as used herein refers to a straight or branchedalkyl group attached to a carbonyl group (alkyl-C(O)—). Exemplaryalkylcarbonyl groups include, but are not limited to, alkylcarbonylgroups of 1-6 atoms, referred to herein as C₁₋₆alkylcarbonyl groups.Exemplary alkylcarbonyl groups include, but are not limited to, acetyl,propanoyl, isopropanoyl, butanoyl, etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond.Exemplary alkynyl groups include, but are not limited to, straight orbranched groups of 2-6, or 3-6 carbon atoms, referred to herein asC₂₋₆alkynyl, and C₃₋₆alkynyl, respectively. Exemplary alkynyl groupsinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, etc.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “cyano” as used herein refers to the radical —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to oxygen (cycloalkyl-O—). Exemplary cycloalkoxy groupsinclude, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms,referred to herein as C₃₋₆cycloalkoxy groups. Exemplary cycloalkoxygroups include, but are not limited to, cyclopropoxy, cyclobutoxy,cyclohexyloxy, etc

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers toa saturated or partially unsaturated hydrocarbon group of, for example,3-6, or 4-6 carbons, referred to herein as C₃₋₆cycloalkyl orC₄₋₆cycloalkyl, respectively. Exemplary cycloalkyl groups include, butare not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutylor cyclopropyl.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The terms “heteroaryl” or “heteroaromatic group” as used herein refersto a monocyclic aromatic 5-6 membered ring system containing one or moreheteroatoms, for example one to three heteroatoms, such as nitrogen,oxygen, and sulfur. Where possible, said heteroaryl ring may be linkedto the adjacent radical though carbon or nitrogen. Examples ofheteroaryl rings include but are not limited to furan, thiophene,pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole,triazole, pyridine or pyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated, 4-10 membered ringstructures, including bridged or fused rings, and whose ring structuresinclude one to three heteroatoms, such as nitrogen, oxygen, and sulfur.Where possible, heterocyclyl rings may be linked to the adjacent radicalthrough carbon or nitrogen. Examples of heterocyclyl groups include, butare not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine,piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

The term “heterocyclyloxy” as used herein refers to a heterocyclyl groupattached to oxygen (heterocyclyl-O—).

The term “heteroaryloxy” as used herein refers to a heteroaryl groupattached to oxygen (heteroaryl-O—).

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical—OH.

The term “oxo” as used herein refers to the radical ═O.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds of the invention can beadministered to a mammal, such as a human, but can also be administeredto other mammals such as an animal in need of veterinary treatment,e.g., domestic animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, sheep, pigs, horses, and the like) and laboratory animals(e.g., rats, mice, guinea pigs, and the like). The mammal treated in themethods of the invention is desirably a mammal in which treatment ofobesity or weight loss is desired. “Modulation” includes antagonism(e.g., inhibition), agonism, partial antagonism and/or partial agonism.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system or animal, (e.g.mammal or human) that is being sought by the researcher, veterinarian,medical doctor or other clinician. The compounds of the invention areadministered in therapeutically effective amounts to treat a disease.Alternatively, a therapeutically effective amount of a compound is thequantity required to achieve a desired therapeutic and/or prophylacticeffect, such as an amount which results in weight loss.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe compositions. Compounds included in the present compositions thatare basic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including, but notlimited to, malate, oxalate, chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds included in the present compositions that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts, particularly calcium, magnesium, sodium,lithium, zinc, potassium, and iron salts. Compounds included in thepresent compositions that include a basic or acidic moiety may also formpharmaceutically acceptable salts with various amino acids. Thecompounds of the disclosure may contain both acidic and basic groups;for example, one amino and one carboxylic acid group. In such a case,the compound can exist as an acid addition salt, a zwitterion, or a basesalt.

The compounds of the disclosure may contain one or more chiral centersand, therefore, exist as stereoisomers. The term “stereoisomers” whenused herein consist of all enantiomers or diastereomers. These compoundsmay be designated by the symbols “(+),” “(−),” “R” or “S,” depending onthe configuration of substituents around the stereogenic carbon atom,but the skilled artisan will recognize that a structure may denote achiral center implicitly. The present invention encompasses variousstereoisomers of these compounds and mixtures thereof. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

The compounds of the disclosure may contain one or more double bondsand, therefore, exist as geometric isomers resulting from thearrangement of substituents around a carbon-carbon double bond. Thesymbol

denotes a bond that may be a single, double or triple bond as describedherein. Substituents around a carbon-carbon double bond are designatedas being in the “Z” or “E” configuration wherein the terms “Z” and “E”are used in accordance with IUPAC standards. Unless otherwise specified,structures depicting double bonds encompass both the “E” and “Z”isomers. Substituents around a carbon-carbon double bond alternativelycan be referred to as “cis” or “trans,” where “cis” representssubstituents on the same side of the double bond and “trans” representssubstituents on opposite sides of the double bond.

Compounds of the disclosure may contain a carbocyclic or heterocyclicring and therefore, exist as geometric isomers resulting from thearrangement of substituents around the ring. The arrangement ofsubstituents around a carbocyclic or heterocyclic ring are designated asbeing in the “Z” or “E” configuration wherein the terms “Z” and “E” areused in accordance with IUPAC standards. Unless otherwise specified,structures depicting carbocyclic or heterocyclic rings encompass both“Z” and “E” isomers. Substituents around a carbocyclic or heterocyclicrings may also be referred to as “cis” or “trans”, where the term “cis”represents substituents on the same side of the plane of the ring andthe term “trans” represents substituents on opposite sides of the planeof the ring. Mixtures of compounds wherein the substituents are disposedon both the same and opposite sides of plane of the ring are designated“cis/trans.”

Individual enantiomers and diasteriomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using stereoselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well known methods, such as chiral-phase liquid chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use ofchiral auxiliaries. For examples, see Carreira and Kvaerno, Classics inStereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. In one embodiment, thecompound is amorphous. In one embodiment, the compound is a singlepolymorph. In another embodiment, the compound is a mixture ofpolymorphs. In another embodiment, the compound is in a crystallineform.

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example,a compound of the invention may have one or more H atom replaced withdeuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the examples herein by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “prodrug” refers to compounds that are transformed in vivo toyield a disclosed compound or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (such as by esterase, amidase, phosphatase, oxidativeand or reductive metabolism) in various locations (such as in theintestinal lumen or upon transit of the intestine, blood or liver).Prodrugs are well known in the art (for example, see Rautio,Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). Forexample, if a compound of the invention or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁₋₈)alkyl, (C₂₋₁₂)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethylhaving from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁₋₂)alkylamino(C₂₋₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁₋₂)alkyl, N,N-di(C₁₋₂)alkylcarbamoyl-(C₁₋₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as (C₁₋₆)alkylcarbonyloxymethyl,1-((C₁₋₆)alkylcarbonyloxy)ethyl,1-methyl-1-((C₁₋₆)alkylcarbonyloxy)ethyl (C₁₋₆)alkoxycarbonyloxymethyl,N—(C₁₋₆)alkoxycarbonylaminomethyl, succinoyl, (C₁₋₆)alkylcarbonyl,α-amino(C₁₋₄)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl,or α-aminoalkylcarbonyl-α-aminoalkylcarbonyl, where eachα-aminoalkylcarbonyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

If a compound of the invention incorporates an amine functional group, aprodrug can be formed, for example, by creation of an amide orcarbamate, an N-alkylcarbonyloxyalkyl derivative, an(oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.In addition, a secondary amine can be metabolically cleaved to generatea bioactive primary amine, or a tertiary amine can metabolically cleavedto generate a bioactive primary or secondary amine. For examples, seeSimplicio, et al., Molecules 2008, 13, 519 and references therein.

I. Tricyclic Compounds

In certain embodiments, the present invention provides compounds ofFormula I or Formula II:

wherein

-   -   B¹ may be a 3-6 membered saturated or partially unsaturated        heterocyclic or carbocyclic ring;    -   B² may be a 3-6 membered saturated heterocyclic or carbocyclic        ring;    -   wherein the ring B¹ or B² may optionally be substituted by one        or more fluorine atoms on any of the available carbon atoms    -   D¹ may be a 5-7 membered heterocyclic, carbocyclic,        heteroaromatic or aromatic ring;    -   D² may be a 5-7 membered heterocyclic or carbocyclic ring;    -   wherein B¹ is fused to D¹ such that the two atoms shared by B¹        and D¹ are both carbon and B² is fused to D² such that the two        atoms shared by B² and D² are both carbon; and wherein for        Formula I the bond common to both the B¹ and D¹ rings may be a        single or double bond;    -   X¹ may be selected from the group consisting of:        ⁺—C(R^(D1)R^(D2))—*, ⁺—W¹—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*, ⁺—C(R^(C1))═C(R^(C2))—*,        ⁺—W²—C(R^(D5)R^(D6))—*, ⁺—W²—C(O)—*, ⁺—C(R^(D1)R^(D2))—W⁴—*,        ⁺—N═C(R^(C2))—*, ⁺—C(R^(C1))═N—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,        ⁺—W²—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,        ⁺—W²—C(O)—C(R^(D5)R^(D6))—*,        ⁺—C(R^(D1)R^(D2))—W³—C(R^(D5)R^(D6))—*,        ⁺—C(R^(D1)R^(D2))—W³—C(O)—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—W⁴—* and        ⁺—C(R^(D1)R^(D2))—C(O)—W⁴—*; wherein the ⁺ and * indicate the        attachment points of X¹ as indicated in Formula I;    -   X² may be selected from the group consisting of:        ⁺—C(R^(D1)R^(D2))—*, ⁺—W¹—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*, ⁺—W²—C(R^(D5)R^(D6))—*,        ⁺—W²—C(O)— *, ⁺—C(R^(D1)R^(D2))—W⁴—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,        ⁺—W²—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,        ⁺—W²—C(O)—C(R^(D5)R^(D6))—*,        ⁺—C(R^(D1)R^(D2))—W³—C(R^(D5)R^(D6))—*,        ⁺—C(R^(D1)R^(D2))—W³—C(O)—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—W⁴—* and        ⁺—C(R^(D1)R^(D2))—C(O)—W⁴—*; wherein the ⁺ and * indicate the        attachment points of X² as indicated in Formula II;    -   Y may be selected from the group consisting of: a bond,        *—CH₂—^(#), *—O—^(#), *—CH₂—CH₂—^(#), *—O—CH₂—^(#),        *—CH₂—O—^(#), *—CH₂—CH₂—CH₂—^(#), *—O—CH₂—CH₂—^(#) and        *—CH₂—O—CH₂—^(#); wherein the * and ^(#) indicate the attachment        points of Y as indicated in Formula I or Formula II;    -   W¹ may be selected from the group consisting of O, S, or        N(R^(N1));    -   W² may be selected from the group consisting of O or N(R^(N2));    -   W³ may be selected from the group consisting of O or N(R^(N3));    -   W⁴ may be selected from the group consisting of O or N(R^(N4));    -   A may be a ring selected from the group consisting of phenyl, a        5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each        selected from S, N or O, and a 4-7 membered heterocycle having        1, 2 or 3 heteroatoms each selected from N or O;    -   R^(B1) and R^(B2) are independently selected from the group        consisting of H, F, OH, CN, C₁₋₂alkoxy or C₁₋₃alkyl; wherein        C₁₋₃alkyl and C₁₋₂alkoxy are optionally substituted by a group        selected from OH, C₁₋₂alkoxy, CN or one or more fluorine atoms;    -   R^(A1) may be selected, independently for each occurrence, from        the group consisting of hydrogen, hydroxyl, cyano, halogen,        C₁₋₄alkyl or C₁₋₃alkoxy; wherein C₁₋₄alkyl, or C₁₋₃alkoxy may be        optionally substituted by one or more fluorines;    -   n may be 1 or 2;    -   R^(A2) may be selected from the group consisting of hydrogen,        R^(i)R^(j)N—, heterocyclyl, heterocyclyloxy and        heterocyclyl-(NR^(a))—; wherein said heterocyclyl may optionally        be substituted by one or more substituents selected from R^(g)        and wherein if said heterocyclyl contains a —NH moiety that        nitrogen may optionally be substituted by one or more groups        R^(h); or    -   R^(A2) may be selected from the group consisting of: C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,        C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,        C₁₋₆alkyl-S(O)_(w)— (wherein w is 0, 1 or 2),        C₁₋₆alkyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))-carbonyl-,        C₁₋₆alkylcarbonyl-N(R^(a))—,        C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,        C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,        C₁₋₆alkylcarbonyl-N(R^(a))—C₁₋₆alkyl-,        C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxyC₁₋₆alkyl-;        wherein C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₁₋₆alkoxy, C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,        C₁₋₆alkyl-S(O)_(w)—, C₁₋₆alkyl-N(R^(a))—,        C₁₋₆alkyl-N(R^(a))-carbonyl-, C₁₋₆alkylcarbonyl-N(R^(a))—,        C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,        C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,        C₁₋₆alkylcarbonyl-N(R^(a))C₁₋₆alkyl-,        C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxy-C₁₋₆alkyl may        optionally be substituted by R^(P), phenyl, phenoxy, heteroaryl,        heteroaryloxy, heteroaryl-(NR^(a))—, heterocyclyl,        heterocyclyloxy or heterocyclyl-N(R^(a))—; and wherein said        heteroaryl or phenyl may optionally be substituted with one or        more substituents selected from R^(f); and wherein said        heterocyclyl may optionally be substituted by one or more        substituents selected from R^(g); and wherein if said        heterocyclyl contains a —NH moiety that nitrogen may optionally        be substituted by one or more groups R^(h);    -   R^(D1) and R^(D2) may be each independently selected from the        group consisting of hydrogen, fluorine, hydroxyl, C₁₋₂alkyl or        C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy may optionally        be substituted by one or more fluorine atoms or a group selected        from cyano or hydroxyl;    -   R^(D3) and R^(D4) may be each independently selected from the        group consisting of hydrogen, fluorine, hydroxyl, cyano,        C₁₋₃alkyl or C₁₋₃alkoxy; wherein the C₁₋₃ alkyl and C₁₋₃ alkoxy        may optionally be substituted by one or more fluorine atoms or a        group selected from cyano, hydroxyl or N(R^(a)R^(b));    -   R^(D5) and R^(D6) may be each independently selected from the        group consisting of hydrogen, fluorine, hydroxyl, cyano,        C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy        may optionally be substituted by one or more fluorine atoms or a        group selected from cyano, hydroxyl or N(R^(a)R^(b));    -   R^(C1) may be selected from the group consisting of hydrogen,        halogen, C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl or        C₁₋₂alkoxy may optionally be substituted by one or more fluorine        atoms;

R^(C2) may be selected from the group consisting of hydrogen, halogen,hydroxyl, cyano, C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl andC₁₋₂alkoxy may optionally be substituted by one or more fluorine atomsor a group selected from cyano, hydroxyl or N(R^(a)R^(b));

R^(N1) may be selected from the group consisting of hydrogen orC₁₋₂alkyl;

R^(N2) may be selected from the group consisting of hydrogen orC₁₋₂alkyl;

R^(N3) may be selected from the group consisting of hydrogen, C₁₋₃alkylor C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and C₁₋₂alkylcarbonyl mayoptionally be substituted by one or more fluorine atoms or a groupselected from cyano, hydroxyl or N(R^(a)R^(b));

-   -   R^(N4) may be selected from the group consisting of hydrogen,        C₁₋₃alkyl or C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and        C₁₋₂alkylcarbonyl may optionally be substituted by one or more        fluorine atoms or a group selected from cyano, hydroxyl or        N(R^(a)R^(b));    -   R^(a) and R^(b) may be independently selected, for each        occurrence, from the group consisting of hydrogen and C₁₋₃alkyl;        wherein C₁₋₃alkyl may optionally be substituted by one or more        substituents selected from fluorine, cyano, oxo and hydroxyl;    -   or R^(a) and R^(b), together with the nitrogen to which they are        attached, may form a 4-6 membered heterocyclic ring, which may        have an additional heteroatom selected from O, S, or N; wherein        the 4-6 membered heterocyclic ring may optionally be substituted        by one or more substituents selected from the group consisting        of fluorine, cyano, oxo or hydroxyl;    -   R^(f) may be independently selected, for each occurrence, from        the group consisting of R^(P), hydrogen, C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,        C₁₋₆alkyl-S(O)_(w)—, (wherein wherein w is 0, 1 or 2),        C₁₋₆alkylcarbonyl-N(R^(a))— and C₁₋₆alkoxycarbonyl-N(R^(a))—;        wherein C₁₋₆alkyl, C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(w)—, C₁₋₆alkylcarbonyl-N(R^(a))—,        C₁₋₆alkoxycarbonyl-N(R^(a))— may be optionally substituted by        one or more substituents selected from R^(P);    -   R^(g) may be independently selected for each occurrence from the        group consisting of R^(P), hydrogen, oxo, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, (wherein w        is 0, 1 or 2), C₁₋₆alkylcarbonyl-N(R^(a))— and        C₁₋₆alkoxycarbonyl-N(R^(a))—; wherein C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(w)—,        C₁₋₆alkylcarbonyl-N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))— may be        optionally substituted by one or more substituents selected from        R^(P);    -   R^(h) may be independently selected for each occurrence from the        group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,        C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,        C₁₋₆alkoxycarbonyl-, R^(i)R^(j)N-carbonyl- and R^(i)R^(j)N—SO₂—;        wherein C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl C₃₋₆ cycloalkyl and        C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl- may optionally be        substituted by one or more substituents selected from R^(P);    -   R^(i) and R^(j) may be selected independently for each        occurrence from the group consisting of hydrogen, C₁₋₄alkyl        C₃₋₆cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein        C₁₋₄alkyl and C₃₋₆cycloalkyl may be optionally substituted by        one or more substituents selected from fluorine, hydroxyl,        cyano, R^(a)R^(b)N—, R^(a)R^(b)N-carbonyl- and C₁₋₃alkoxy and        wherein heterocyclyl and heterocyclylcarbonyl may be optionally        substituted by one or more substituents selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,        halo-C₁₋₆-alkyl, hydroxyl-C₁₋₆-alkyl, R^(a)R^(b)N—C₁₋₆alkyl- and        C₁₋₆-alkoxy-C₁₋₆-alkyl group; and wherein if said heterocyclyl        or heterocyclylcarbonyl contains a —NH moiety that nitrogen may        optionally be substituted by one or more groups C₁₋₆alkyl,        C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂— and        C₁₋₆-alkylcarbonyl;    -   or R^(i) and R^(j) taken together with the nitrogen to which        they are attached may form a 4-7 membered heterocyclic ring,        which may have an additional heteroatom selected from O, S, or        N; wherein the 4-7 membered heterocyclic ring may be optionally        substituted on carbon by one or more substituents selected from        the group consisting of fluorine, hydroxyl, oxo, cyano,        C₁₋₆alkyl, C₁₋₆alkoxy, R^(a)R^(b)N—, R^(a)R^(b)N—SO₂— and        R^(a)R^(b)N-carbonyl-; wherein said C₁₋₆alkyl or C₁₋₆alkoxy may        optionally be substituted by fluorine, hydroxyl or cyano; and        wherein the 4-7 membered heterocyclic ring may be optionally        substituted on nitrogen by one or more substituents selected        from the group consisting of C₁₋₆alkyl and        R^(a)R^(b)N-carbonyl-; and wherein said C₁₋₆alkyl may be        optionally substituted by fluorine, hydroxyl, cyano;    -   R^(P) may be independently selected, for each occurrence, from        the group consisting of halogen, hydroxyl, cyano, C₁₋₆alkoxy,        R^(i)R^(j)N—, R^(i)R^(j)N-carbonyl-, R^(i)R^(j)N—SO₂— and        R^(i)R^(j)N-carbonyl-N(R^(a))—;        and pharmaceutically acceptable salts, stereoisomers, esters and        prodrugs thereof

In some embodiments, X¹ may be selected from the group consisting of:⁺—O—*, ⁺—N(R^(N1))—*, ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*,⁺—C(R^(C1))═C(R^(C2))—*, ⁺—O—C(R^(D5)R^(D6))—*,⁺—N(R^(N2))—C(R^(D5)R^(D6))—*, ⁺—O—C(O)—*, ⁺—N(R^(N2))—C(O)—*,⁺—N═C(R^(C2))—* and ⁺—O—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*; wherein the ⁺and * indicate the attachment points of X¹ as indicated in Formula I.Exemplary X¹ moities may be selected from the group consisting of:⁺—NH—*, ⁺—O—CH₂—*, ⁺—NH—CH₂—*, ⁺—N═CH—* and ⁺—CH═CH—*; wherein the ⁺and * indicate the attachment points of X¹ as indicated in Formula I.

In some embodiments X² may be selected from the group consisting of⁺—O—*, ⁺—N(R^(N1))—*, ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*,⁺—O—C(R^(D5)R^(D6))—*, ⁺—N(R^(N2))—C(R^(D5)R^(D6))—*, ⁺—O—C(O)—*,⁺—N(R^(N2))—C(O)—*, and ⁺—O—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*; whereinthe ⁺ and * indicate the attachment points of X² as indicated in FormulaII. Exemplary X² moities may be selected from the group consisting of:⁺—O—CH₂—* and ⁺—NH—CH₂—*; wherein the ⁺ and * indicate the attachmentpoints of X² as indicated in Formula II.

In one embodiment, R^(D1), R^(D2), R^(C1), R^(N1) and R^(N2) may beindependently selected for each occurrence from the group consisting ofhydrogen and methyl. For example, R^(D1), R^(D2), R^(C1), R^(N1) andR^(N2) may be hydrogen.

In certain embodiments, R^(D3), R^(D4), R^(D5) and R^(D6) may beindependently selected for each occurrence from the group consisting ofhydrogen, fluorine, cyano and C₁₋₂alkyl. For example, R^(D3), R^(D4),R^(D5) and R^(D6) may be hydrogen.

In an embodiment, R^(C2) may be selected from the group consisting ofhydrogen, halogen, cyano and C₁₋₂alkyl. For example, R^(C2) may behydrogen.

In certain embodiments, R^(B1) of the tricyclic compound of Formula IImay be selected from the group consisting of H, F or C₁₋₂alkyl. Forexample, R^(B1) may be H or methyl.

In another embodiment, R^(B2) of the tricyclic compound of Formula IImay be hydrogen.

In certain embodiments, ring D¹ may be selected from the groupconsisting of:

wherein the *, # and + indicate the points of attachment to the phenylring and the B¹ ring as indicated in Formula I. Exemplary D¹ rings thatmay form part of the contemplated tricyclic core may include thoseselected from the group consisting of:

In certain embodiments, ring D² may be selected from the groupconsisting of:

wherein the *, # and + indicate the points of attachment to the phenylring and the B² ring as indicated in Formula II.

In some embodiments, Y may be selected from the group consisting of abond, *—O—CH₂ ^(#) and *—CH₂—O—CH₂—^(#); wherein the * and # indicatethe points of attachment to Y as indicated in Formula I or Formula II.For example, Y may be a bond or *—O—CH₂ ^(#); wherein the * and #indicate the points of attachment to Y as indicated in Formula I orFormula II.

For example, ring B¹ or B² may, in certain embodiments, be selected fromthe group consisting of:

wherein the * and # indicate the points of attachment to Y as indicatedin Formula I and II. Exemplary B¹ and B² rings that may form part of thecontemplated tricyclic core may include those selected from the groupconsisting of:

Also provided herein is a compound represented by Formula IV:

-   -   D² may be a 5-7 membered partially unsaturated heterocyclic or        carbocyclic ring;    -   X² may be selected from the group consisting of:        ⁺—C(R^(D1)R^(D2))—*, ⁺—W¹—* ⁺—C(R^(D1)R^(D2))—C(R^(D5)R^(D6))—*,        ⁺—W²—C(R^(D5)R^(D6))—*, ⁺—W²—C(O)—*, ⁺—C(R^(D1)R^(D2))—W⁴—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,        ⁺—W²—C(R^(D3)R^(D4))—C(R^(D5)R^(D6))—*,        ⁺—W²—C(O)—C(R^(D5)R^(D6))—*,        ⁺—C(R^(D1)R^(D2))—W³—C(R^(D5)R^(D6))—*,        ⁺—C(R^(D1)R^(D2))—W³—C(O)—*,        ⁺—C(R^(D1)R^(D2))—C(R^(D3)R^(D4))—W⁴—* and        ⁺—C(R^(D1)R^(D2))—C(O)—W⁴—*; wherein the ⁺ and * indicate the        attachment points of X² as indicated in Formula IV;    -   W¹ may be selected from the group consisting of O, S or        N(R^(N1));    -   W² may be selected from the group consisting of O or N(R^(N2));    -   W³ may be selected from the group consisting of O or N(R^(N3));    -   W⁴ may be selected from the group consisting of O or N(R^(N4));    -   R^(B1) may be selected from the group consisting of H, F, OH,        CN, C₁₋₂alkoxy or C₁₋₃alkyl; wherein C₁₋₃alkyl and C₁₋₂alkoxy        are optionally substituted by a group selected from OH,        C₁₋₂alkoxy, CN or one or more fluorine atoms;    -   R^(A1) may be selected, independently for each occurrence, from        the group consisting of hydrogen, hydroxyl, cyano, halogen,        C₁₋₄alkyl or C₁₋₃alkoxy; wherein C₁₋₄alkyl, or C₁₋₃alkoxy may be        optionally substituted by one or more fluorines;    -   n may be 0, 1, or 2;    -   R^(A2) may be selected from the group consisting of hydrogen,        R^(i)R^(j)N—, heterocyclyl, heterocyclyloxy and        heterocyclyl-(NR^(a))—; wherein said heterocyclyl may optionally        be substituted by one or more substituents selected from R^(g)        and wherein if said heterocyclyl contains a —NH moiety that        nitrogen may optionally be substituted by one or more groups        R^(h); or    -   R^(A2) may be selected from the group consisting of: C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,        C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,        C₁₋₆alkyl-S(O)_(w)— (wherein w is 0, 1 or 2),        C₁₋₆alkyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))-carbonyl-,        C₁₋₆alkylcarbonyl-N(R^(a))—,        C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,        C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,        C₁₋₆alkylcarbonyl-N(R^(a))—C₁₋₆alkyl-,        C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxyC₁₋₆alkyl-;        wherein C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,        C₁₋₆alkoxy, C₃₋₆alkenyloxy, C₃₋₆alkynyloxy, C₃₋₆cycloalkoxy,        C₁₋₆alkyl-S(O)_(w)—, C₁₋₆alkyl-N(R^(a))—,        C₁₋₆alkyl-N(R^(a))-carbonyl-, C₁₋₆alkylcarbonyl-N(R^(a))—,        C₁₋₆alkyl-N(R^(a))-carbonyl-N(R^(a))—, C₁₋₆alkyl-N(R^(a))—SO₂—,        C₁₋₆alkyl-SO₂—N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))—,        C₁₋₆alkylcarbonyl-N(R^(a))C₁₋₆alkyl-,        C₁₋₆alkyl-N(R^(a))-carbonyl-C₁₋₆alkyl-, C₁₋₆alkoxy-C₁₋₆alkyl may        optionally be substituted by R^(P), phenyl, phenoxy, heteroaryl,        heteroaryloxy, heteroaryl-(NR^(a))—, heterocyclyl,        heterocyclyloxy or heterocyclyl-N(R^(a))—; and wherein said        heteroaryl or phenyl may optionally be substituted with one or        more substituents selected from R^(f); and wherein said        heterocyclyl may optionally be substituted by one or more        substituents selected from R^(g); and wherein if said        heterocyclyl contains a —NH moiety that nitrogen may optionally        be substituted by one or more groups R^(h);    -   R^(D1) and R^(D2) may be each independently selected from the        group consisting of hydrogen, fluorine, hydroxyl, C₁₋₂alkyl or        C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy may optionally        be substituted by one or more fluorine atoms or a group selected        from cyano or hydroxyl;    -   R^(D3) and R^(D4) may be each independently selected from the        group consisting of hydrogen, fluorine, hydroxyl, cyano,        C₁₋₃alkyl or C₁₋₃alkoxy; wherein the C₁₋₃ alkyl and C₁₋₃ alkoxy        may optionally be substituted by one or more fluorine atoms or a        group selected from cyano, hydroxyl or N(R^(a)R^(b));    -   R^(D5) and R^(D6) may be each independently selected from the        group consisting of hydrogen, fluorine, hydroxyl, cyano,        C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl and C₁₋₂alkoxy        may optionally be substituted by a substituent or substituents        selected from the group consisting of: one or more fluorine        atoms, cyano, hydroxyl or N(R^(a)R^(b));

R^(C1) may be selected from the group consisting of hydrogen, halogen,C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl or C₁₋₂alkoxy mayoptionally be substituted by one or more fluorine atoms;

R^(C2) may be selected from the group consisting of hydrogen, halogen,hydroxyl, cyano, C₁₋₂alkyl or C₁₋₂alkoxy; wherein the C₁₋₂alkyl andC₁₋₂alkoxy may optionally be substituted by one or more fluorine atomsor a group selected from cyano, hydroxyl or N(R^(a)R^(b));

-   -   R^(N1) may be selected from the group consisting of hydrogen or        C₁₋₂alkyl;    -   R^(N2) may be selected from the group consisting of hydrogen or        C₁₋₂alkyl;    -   R^(N3) may be selected from the group consisting of hydrogen,        C₁₋₃alkyl or C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and        C₁₋₂alkylcarbonyl may optionally be substituted by a substituent        or substituents selected from the group consisting of: one or        more fluorines, cyano, hydroxyl or N(R^(a)R^(b));    -   R^(N4) may be selected from the group consisting of hydrogen,        C₁₋₃alkyl or C₁₋₂alkylcarbonyl; wherein the C₁₋₃alkyl and        C₁₋₂alkylcarbonyl may optionally be substituted by a substituent        or substituents selected from the group consisting of: one or        more fluorines, cyano, hydroxyl or N(R^(a)R^(b));    -   R^(a) and R^(b) may be independently selected, for each        occurrence, from the group consisting of hydrogen and C₁₋₃alkyl;        wherein C₁₋₃alkyl may optionally be substituted by one or more        substituents selected from fluorine, cyano, oxo and hydroxyl;    -   or R^(a) and R^(b), together with the nitrogen to which they are        attached, may form a 4-6 membered heterocyclic ring, which may        have an additional heteroatom selected from O, S, or N; wherein        the 4-6 membered heterocyclic ring may optionally be substituted        by one or more substituents selected from the group consisting        of fluorine, cyano, oxo or hydroxyl;    -   R^(f) may be independently selected, for each occurrence, from        the group consisting of R^(P), hydrogen, C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, (wherein w        is 0, 1 or 2), C₁₋₆alkylcarbonyl-N(R^(a))— and        C₁₋₆alkoxycarbonyl-N(R^(a))—; wherein C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,        C₁₋₆alkylcarbonyl-N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))— may be        optionally substituted by one or more substituents selected from        R^(P);    -   R^(g) may be independently selected for each occurrence from the        group consisting of R^(P), hydrogen, oxo, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, (wherein w is 0, 1 or        2), C₁₋₆alkylcarbonyl-N(R^(a))— and        C₁₋₆alkoxycarbonyl-N(R^(a))—; wherein C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkyl-S(O)_(w)—,        C₁₋₆alkylcarbonyl-N(R^(a))—, C₁₋₆alkoxycarbonyl-N(R^(a))— may be        optionally substituted by one or more substituents selected from        R^(P);    -   R^(h) may be independently selected for each occurrence from the        group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,        C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂—,        C₁₋₆alkoxycarbonyl-, R^(i)R^(j)N-carbonyl- and R^(i)R^(j)N—SO₂—;        wherein C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl C₃₋₆cycloalkyl and        C₁₋₆alkyl-S(O)₂—, C₁₋₆alkylcarbonyl- may optionally be        substituted by one or more substituents selected from R^(P);    -   R^(i) and R^(j) may be selected independently for each        occurrence from the group consisting of hydrogen, C₁₋₄alkyl        C₃₋₆cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein        C₁₋₄alkyl and C₃₋₆cycloalkyl may be optionally substituted by        one or more substituents selected from fluorine, hydroxyl,        cyano, R^(a)R^(b)N—, R^(a)R^(b)N-carbonyl- and C₁₋₃alkoxy and        wherein heterocyclyl and heterocyclylcarbonyl may be optionally        substituted by one or more substituents selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,        halo-C₁₋₆-alkyl, hydroxyl-C₁₋₆ alkyl and C₁₋₆-alkoxy-C₁₋₆-alkyl        group; and wherein if said heterocyclyl or heterocyclylcarbonyl        contains a —NH moiety that nitrogen may optionally be        substituted by one or more groups C₁₋₆alkyl, C₃₋₆alkenyl,        C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkyl-S(O)₂— and        C₁₋₆-alkylcarbonyl;    -   or R^(i) and R^(j) taken together with the nitrogen to which        they are attached may form a 4-7 membered heterocyclic ring,        which may have an additional heteroatom selected from O, S, or        N; wherein the 4-7 membered heterocyclic ring may be optionally        substituted on carbon by one or more substituents selected from        the group consisting of fluorine, hydroxyl, oxo, cyano,        C₁₋₆alkyl, C₁₋₆alkoxy, R^(a)R^(b)N—, R^(a)R^(b)N—SO₂— and        R^(a)R^(b)N-carbonyl-; wherein said C₁₋₆alkyl or C₁₋₆alkoxy may        optionally be substituted by fluorine, hydroxyl or cyano; and        wherein the 4-7 membered heterocyclic ring may be optionally        substituted on nitrogen by one or more substituents selected        from the group consisting of C₁₋₆alkyl and        R^(a)R^(b)N-carbonyl-; and wherein said C₁₋₆alkyl may be        optionally substituted by one or more substituents selected from        the group consisting of fluorine, hydroxyl, cyano;    -   R^(P) may be independently selected, for each occurrence, from        the group consisting of halogen, hydroxyl, cyano, C₁₋₆alkoxy,        R^(i)R^(j)N—, R^(i)R^(j)N-carbonyl-, R^(i)R^(j)N—SO₂— and        R^(i)R^(j)N-carbonyl-N(R^(a))—;    -   and pharmaceutically acceptable salts, stereoisomers, esters and        prodrugs thereof

In certain embodiments, R^(A1) of the tricyclic compound of Formula IVmay be hydrogen or fluorine.

In another embodiment, R^(A2) of the tricyclic compound of Formula IVmay be selected from the group consisting of hydrogen, R^(i)R^(j)N,heterocyclyl, C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,heterocyclyl-NR^(a)-carbonyl-C₁₋₆alkyl andheterocyclyl-carbonyl-NR^(a)—C₁₋₆alkyl; wherein said heterocyclyl mayoptionally be substituted by one or more groups R^(g); and wherein ifsaid heterocyclyl contains a —NH moiety, that nitrogen may optionally besubstituted by on or more groups R^(h); and wherein said C₁₋₆alkyl,C₃₋₆alkenyl, C₃₋₆cycloalkyl and C₁₋₆alkoxy may optionally be substitutedby one or more groups R^(P).

Also provided herein are compounds that may be selected from the groupconsisting of(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid, or enantiomers thereof;(1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid, or enantiomers thereof;(1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-(4-fluoro-2-[(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-(4-fluoro-2-[(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[(((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino-methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid-formic acid (1:1);(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid-formic acid (1:1) and pharmaceutically acceptable salts,stereoisomers, esters and prodrugs thereof.

Procedures for making compounds described herein are provided below withreference to Schemes 1-3. In the reactions described below, it may benecessary to protect reactive functional groups (such as hydroxyl,amino, thio or carboxyl groups) to avoid their unwanted participation inthe reactions. The incorporation of such groups, and the methodsrequired to introduce and remove them are known to those skilled in theart (for example, see Greene, Wuts, Protective Groups in OrganicSynthesis. 2nd Ed. (1999)). The deprotection step may be the final stepin the synthesis such that the removal of protecting groups affordscompounds of Formula I, as disclosed herein, or as exemplified in, forexample, General Formula I, below. Starting materials used in thefollowing schemes can be purchased or prepared by methods described inthe chemical literature, or by adaptations thereof, using methods knownby those skilled in the art. The order in which the steps are performedcan vary depending on the groups introduced and the reagents used, butwould be apparent to those skilled in the art.

The general synthetic strategy used to prepare the tricyclic compoundsof General Formula I is depicted in Scheme 1. The tricyclic system maybe assembled in a variety of ways, starting from an appropriatelysubstituted and protected phenyl ring 1A. The group G′ is a suitablyprotected carboxylic acid, such as a methyl- or t-butyl carboxylate oris a functional group that may be readily converted into a carboxylicacid, such as a nitrile or aldehyde. The group G is a sulfonamide group,or a functional group that may be subsequently converted into asulfonamide group such as a suitably protected aniline. The B′-ring canbe directly attached to the substituted phenyl ring to give intermediate1B, and then the D′-ring can be formed by an intra-molecular reaction togive intermediate 1E. Alternatively, the B′-ring can be attached to thesubstituted phenyl ring 1A via a linker, X′, to give intermediate 1C,and then the D′-ring can be formed by an intra-molecular reaction togive intermediate 1E. Alternatively, the D′-ring can be built up ontothe substituted phenyl ring to give intermediate 1D, and then theB′-ring assembled to give intermediate 1E. Modifications to the B′ andD′ rings may be necessary to provide the required saturated or partiallyunsaturated ring systems and this may be carried out prior to theformation of the tricyclic core or after it. For example, if the B′ ringis a dihydro- or tetrahydrofuran it may be prepared from a correspondingfuran compound by hydrogenation in the presence of a metal catalyst (forexample palladium or palladium hydroxide on a solid support such ascarbon) in a solvent (such as ethyl acetate, ethanol or dioxane)optionally in the presence of an acid (such as acetic acid). Thehydrogenation may be carried out at any stage during the synthesis ofthe compounds either before or after the formation of the tricycliccore. Compounds of Formula I can be prepared from intermediate 1E byremoval of any protecting groups. Alternatively, further modificationsmay be made to 1E, such as modifications at G, before the removal of anyprotecting groups to give compounds of General Formula I. Specific stepsin the synthetic process are described in more detail below.

In Scheme 1, Step (i), compounds of structure 1A may be coupled under arange of conditions to compounds of structure 1B′, where B′ is anappropriate ring to afford compounds of the type 1B. The introduction ofthe B′ ring may require a number of steps and the preparation of anumber of intermediates. Protecting groups may also be required. If R¹is a suitable group (such as a halide or triflate), 1B′ can be convertedto 1B by formation of a carbon-carbon bond. The carbon-carbon bond canbe formed by reacting compounds of structure 1B′ where R³ is a borane,boronate or boronic acid group (such as a 2-formylfuran-3-boronate) inthe presence of a palladium catalyst (such as palladium chloride dppf ortris-(dibenzylideneacetone)-dipalladium), in the presence of a base(such as cesium carbonate) and a suitable reagent (such as a phosphine,for example, tri-tert-butyl-phosphonium tetrafluoroborate ortriphenylphosphine) in an appropriate solvent (such as dioxane, water ortetrahydrofuran, or mixtures thereof) and under appropriate conditions(such as heating, for example heating at 80-120° C. for 1-2 hours ormicrowave irradiation at 120-160° C. for 10 minutes to 1 hour) to afford1B. A wide range of appropriate reagents and conditions are known tothose skilled in the art to couple organoboranes, boronates and boronicacids to compounds such as 1A. [For example, see Miyaura, Suzuki, Chem.Rev. 1995, 95, 2457; Suzuki, Modern Arene Chemistry 2002, 53-106].

Alternatively the carbon-carbon bond in Scheme 1, Step (i) can be formedby coupling compounds of structure 1B′ in which B′ is an appropriatering and where R³ is a trialkylstannane (such as a tri-n-butylstannane)with compounds of structure 1A where R¹ is a suitable group (such as ahalide of triflate) in the presence of a palladium catalyst (such aspalladium chloride dppf), in an appropriate solvent (such asdimethoxyethane or tetrahydrofuran) and under appropriate conditions(such as heating, at 80-120° C. for 1-2 hours or by microwaveirradiation at 120-160° C. for 10 minutes to 1 hour) to afford 1B. Awide range of appropriate reagents and conditions are known to thoseskilled in the art to couple stannanes to aryl halides such as 1A. [Forexample, see Smith, March, March's Advanced Organic Chemistry, 5^(th)Edition, Wiley: New York, 2001, pp. 931-932; De Souza, Current OrganicSynthesis 2006, 3(3), 313-326.].

Alternatively compounds of structure 1A, where R¹ is a suitable group(such as a halide or triflate), can be treated with, for example, adiboronate (such as bis-pinacolatodiboron) in the presence of apalladium catalyst (such as palladium chloride dppf) and a base (such aspotassium acetate or diisopropylamine) in an appropriate solvent (suchas a mixture of dioxane and water) and under appropriate conditions(such as heating, for example at 80-120° C. for 1-2 hours or bymicrowave irradiation at 120-160° C. for 10 minutes to 1 hour) to give acompound of structure 1A, where R¹ is a boronate. A wide range ofappropriate reagents and conditions are known to those skilled in theart to convert an aryl halide (or aryl triflate) to an arylboronate (oran arylborane) [for example, see Marshall Chemtracts 2000, 13(4),219-222]. The arylboronate (or arylborane) thus formed, can then betreated with compounds of structure 1B′ (where R³ is a halogen ortriflate) in the presence of suitable reagents such as a phosphine (forexample tri-tert-butyl-phosphonium tetrafluoroborate), a base (such ascesium carbonate) and a catalyst (such astris-(dibenzylideneacetone)-dipalladium) in an appropriate solvent (suchas a mixture of water and dioxane) under appropriate conditions (such asheating at 80-120° C. for 1-2 hours or by microwave irradiation at120-160° C. for 10 minutes to 1 hour) to afford compounds of structure1B.

In Scheme 1, Step (iv), the groups R² and R⁴ of compound 1B can becoupled together to give the group X′, which forms the D′-ring. R² or R⁴may have been masked by protecting groups during Step (i), and mayrequire deprotection before the group X′ can be formed. Alternatively,R² or R⁴ may require chemical modification before the group X′ can beformed. For example if R² or R⁴ is a nitro group, that group may bereduced, for example using hydrogen in the presence of a suitablecatalyst (such as palladium on a solid support, such as carbon); or bytreatment with an inorganic reducing agent (such as tin (II) chloride inDMF) to give an amino group. For example, if R² or R⁴ is a hydroxyalkylgroup, that group may be treated with an oxidising agent (such as Jonesreagent or manganese dioxide) to give an aldehyde; or with a differentoxidising agent (such as potassium permanganate) to give a carboxylicacid. For example, if R² or R⁴ is an aldehyde, that group may be treatedwith an oxidising agent (such as potassium permanganate) to give acarboxylic acid or with a reducing agent (such as sodium borohydride) togive an alcohol. For example, if R² or R⁴ is a ketone, that group may betreated with a reducing agent (such as sodium borohydride) to give asecondary alcohol. For example, if R² or R⁴ is a carboxylic acid orester, that group may be treated with a reducing agent (such as lithiumaluminium hydride) to give an alcohol. For example, if R² or R⁴ is analkene group, that group may be treated with a borane (such as9-borobicyclononane) and converted to a primary or secondary alcohol.

Formation of the linker X′ may be carried out in a number of ways knownto those skilled in the art. For example, if one of the two groups R²and R⁴ is a hydroxyl and the other is a substituted alkylalcohol then 1Bcan be treated with a dehydrating agent (such as diisopropylazodicarboxylate) in the presence of a phosphine, (such astriphenylphosphine) to give 1E, where X′ is an ether. Alternatively, ifone of the two groups R² or R⁴ is a hydroxyl and the other group is analkyl group substituted with a leaving group (such as a halogen,tosylate or triflate) 1B can be treated with a base (such asdiisopropylethylamine, potassium carbonate or sodium hydride) to form1E, where X′ is an ether.

Alternatively, if one of the groups R² or R⁴ is a carboxylic acid andthe other group is an alkyl halide or sulfonate, then 1B can be treatedwith a base such as diisopropylethylamine, potassium carbonate or sodiumhydride to form 1E, where X′ is an ester.

Alternatively, if one of the two groups R² or R⁴ is a hydroxyl, orsubstituted alkylalcohol and the other group is a carboxylic acid orcarboxylic ester, then 1B can be treated with an acid (such ashydrochloric acid) or dehydrating agent (such asdicyclohexylcarbodiimide or acetic anhydride) to form 1E, where X′ is anester.

Alternatively, if one of the two groups R² or R⁴ on 1B is a hydroxyl orsubstituted alkylalcohol and the other group is a carboxylic acid, thenthe carboxylic acid can first be converted to a mixed anhydride (forexample by treatment with 2,4,6-trichlorobenzoyl chloride) or to anactivated ester (for example by treatment with HATU in the presence of abase such as diisopropylethylamine or pyridine), and the resulting mixedanhydride or activated ester can be further treated with a base (such asdiisopropylethylamine, pyridine or potassium carbonate) to form 1E,where X′ is an ester.

Alternatively, if one of the groups R² or R⁴ on 1B is an amine or asubstituted alkylamine and the other group is a carboxylic acid, thecarboxylic acid can be converted to an activated ester (for example bytreatment with HATU and a base such as diisopropylethylamine or pyridineor TBTU in the presence of N-methylmorpholine), and the resultingactivated ester can be further treated with a base to form 1E where X′is an amide.

Alternatively, if one of the two groups R² or R⁴ on 1B is an amine, or asubstituted alkylamine and the other group is a carboxylic acid, then 1Bcan then be treated with a dehydrating agent (such as such asdiisopropylcarbodiimide) to form 1E, where X′ is an amide.

Alternatively, if one of the two groups R² or R⁴ is an amine, orsubstituted alkylamine and the other group is an alkyl group substitutedwith a leaving group (such as a halogen, tosylate or triflate) then 1Bcan be treated with a base (such as diisopropylethylamine, pyridine orpotassium carbonate) to form 1E, where X′ is a substituted amine.

Alternatively, if one of the two groups R² or R⁴ is an aldehyde, and theother group is a phosphorane (such as an alkyl triphenylphosphorane) oran alkyl phosphonate (such as an alkyl phosphonic acid diethyl ester)then 1B can be treated with a base (such as diisopropylethylamine,potassium carbonate or sodium hexamethyldisilazide) to form 1E, where X′is an alkene which may, or may not be further substituted.

Alternatively, if one of the two groups R² or R⁴ is an amine and theother group is an aldehyde then 1B can be treated with an acid (such asp-toluenesulfoniic acid) or a Lewis acid (such as tin tetrachloride) togive 1E, where X′ is —CR═N— or —N═CR—.

In Scheme 1, Step (ii), compounds of the structure 1A can be reactedwith 1C′ to form the linker X′ and give compounds of the structure 1C.The formation of the linker X′ in compounds with the structure 1C mayrequire a number of steps and the preparation of a number ofintermediates, and the use of protecting groups may also be required.

For example, if one of the two groups R² or R⁶ is a hydroxyl group andthe other group is a substituted alkylalcohol then 1A and 1C′ can betreated with a dehydrating agent (such as diisopropyl azodicarboxylate)in the presence of a phosphine, (such as triphenylphosphine) to give 1C,where X′ is an ether. Alternatively, if one of the two groups R² or R⁴is a hydroxyl and the other group is an alkyl group substituted with aleaving group (such as a halogen, or a mesylate) 1A and 1C′ can betreated with a base (such as diisopropylethylamine, potassium carbonateor sodium hydride) to form 1C, where X′ is an ether.

Alternatively, in Scheme 1, Step (ii), if one of the two groups R² or R⁶is a hydroxyl, or alkylalcohol and the other group is a carboxylic acid,then the carboxylic acid can be converted to an acyl halide (for exampleby treatment with thionyl chloride or oxalyl chloride), or to a mixedanhydride (for example by treatment with 2,4,6-trichlorobenzoyl chloridein the presence of a base such as diisopropylethylamine) or to anactivated ester (for example by treatment with HATU in the presence of abase such as diisopropylethylamine or pyridine, or treatment withdiisopropylcarbodiimide in the presence of HOBT), then 1A and 1C′ can becombined to form 1C, where X′ is an ester.

Alternatively, if one of the two groups R² or R⁶ is an amine, oralkylamine and the other group is a carboxylic acid, then the carboxylicacid can be converted to an acyl halide (for example by treatment withthionyl chloride or oxalyl chloride), or to a mixed anhydride (forexample by treatment with 2,4,6-trichlorobenzoyl chloride in thepresence of a base such as diisopropylethylamine), or to an activatedester (for example by treatment with HATU in the presence ofdisopropylethylamine or pyridine, or treatment withdiisopropylcarbodiimide in the presence of HOBT), then 1A and 1C′ can becombined to form 1C, where X′ is an amide.

Alternatively, if one of the two groups R² or R⁶ is an amine, orsubstituted alkylamine and the other group is an alkyl group substitutedwith a leaving group (such as a halogen, or a triflate) then 1A and 1C′can be treated with a base (such as diisopropylethylamine, pyridine orpotassium carbonate) to form 1C, where X′ is a substituted amine

Alternatively, if one of the two groups R² or R⁶ is an aldehyde, and theother group is a phosphorane (such as an alkyltriphenylphosphorane) oran alkylphosphonate (such as an alkylphosphonic acid diethyl ester) then1A and 1C′ can be treated with a base (such as diisopropylethylamine orpotassium carbonate or sodium hexamethyldisilazide) to form 1C, where X′is an alkene which may, or may not be further substituted.

In Scheme 1, Step (v), compounds of structure 1E may be prepared fromcompounds of structure 1C by reaction of the groups R¹ and R⁵ under arange of conditions to form a carbon-carbon bond. If one of the groupsR¹ or R⁵ is a suitable group (such as a halide or triflate), and theother group is a borane, boronate or boronic acid then, in the presenceof a palladium catalyst (such as palladium chloride dppf), and in thepresence of a base (such as cesium carbonate), in an appropriate solvent(such as dioxane, water or tetrahydrofuran or mixtures thereof) andunder appropriate conditions (such as heating, for example heating at80-120° C. for 1-2 hours or microwave irradiation at 120-160° C. for 10minutes to 1 hour), 1C can be converted into 1E. A wide range ofappropriate reagents and conditions are known to those skilled in theart to couple organoboranes, boronates and boronic acids to givecompounds of the type 1E.

Alternatively, if one of the groups R¹ or R⁵ is a suitable group (suchas a halide or triflate), and the other group is a trialkylstannane, thecarbon-carbon bond can be formed in the presence of a palladium catalyst(such as palladium chloride dppf), in an appropriate solvent (such asdimethoxyethane or tetrahydrofuran) and under appropriate conditions(such as heating, at 80-120° C. for 1-2 hours or by microwaveirradiation at 120-160° C. for 10 minutes to 1 hour) to afford 1E. Awide range of appropriate reagents and conditions are known to thoseskilled in the art to couple aryl or heteroaryl stannanes to aryl orheteroaryl halides.

In Scheme 1, Step (iii), compounds of structure 1A may be reacted undera range of conditions with intermediates of the type 1D′ to givecompounds of structure 1D where D′ is a six- or seven-membered fusedheterocyclic ring and R⁹ and R¹⁰ are suitable functional groups that maybe used to form the B′-ring. The groups R¹ and R⁷ may be reactedtogether to form a carbon-carbon bond, and the groups R² and R⁸ may bereacted together to form the group X′. Methods to form bicycliccompounds of structure 1D from substituted phenyl rings of structure 1Aare well known to those skilled in the art (see ComprehensiveHeterocyclic Chemistry Ed.: Katritzky, Ramsden, Scriven, and Taylor,Elsevier, 2008).

For example, a compound of structure 1A, where R² is a hydroxyl groupand R¹ is hydrogen, can be treated with a suitably protected andsubstituted 3-halo-propanoic acid or ester in an appropriate solvent(such as tetrahydrofuran or dimethylformamide) and in the presence of abase (such as sodium carbonate or diisopropylethylamine) at atemperature between room temperature and the reflux temperature of thesolvent to give a compound of the type 1A, where R² is a substitutedoxypropanoic acid or ester. This intermediate may be treated with asuitable reagent (such as a strong acid, for example triflic acid) togive 1D where R⁹ is oxo, R¹⁰ is hydrogen and X′ is —OCH₂—.

Alternatively, a compound of structure 1A, where R² is a hydroxyl and R¹is hydrogen, can be treated with a propargyl halide or tosylate in thepresence of a base (such as potassium carbonate or cesium carbonate) ina solvent (such as acetone) at a temperature between room temperatureand the reflux temperature of the solvent to give a compound of type 1Ain which R² is a propargyloxyl group. This intermediate may be heated to˜200° C. or treated with an appropriate catalyst (such as a goldcatalyst, for example triphenylphosphine gold triflamide) in anappropriate solvent (such as toluene) at a temperature between 80° C.and the reflux temperature of the solvent to give a compound ofstructure 1D wherein X′ is —OCH₂—, R⁹ and R¹⁰ are H and the bond betweenis a double bond (i.e. a chromene).

Further modification of the intermediates of structure 1D having adouble bond between the carbons that R⁹ and R¹⁰ are attached to (such asa chromene) may be achieved, for example, by treatment with ahydroborating agent (such as borane-THF complex) followed by oxidationwith, for example, hydrogen peroxide to give a mixture of compounds ofstructure 1D wherein X′ is OCH₂, R⁹ is H and R¹⁰ is a hydroxyl group andwherein X′ is —OCH₂—, R⁹ is a hydroxyl and R¹⁰ is H which may beseparated by chromatography.

Further modification of an intermediate of structure 1D in which one ofR⁹ and R¹⁰ is H and the other is a hydroxyl may be carried out. Forexample, the intermediate may be oxidized by treatment with an oxidizingagent (such as Dess Martin periodinane) to give a compound of structure1D in which one of R⁹ and R¹⁰ is H the other is oxo.

Alternatively, a compound of structure 1A in which R¹ is an appropriategroup (such as a halogen, for example bromine or iodine, or a triflate)and R² is a protected amine (such as an acetamide or atrifluoroacetamide) may be coupled with a terminal alkyne in thepresence of a palladium catalyst (such as tetrakis(triphenylphosphine)palladium (0)) optionally in the presence of an additional coppercatalyst (such as copper (I) iodide) in the presence of a base or salt(such as triethylamine or potassium acetate), in a solvent (such astetrahydrofuran or dimethylformamide) at a temperature between roomtemperature and the reflux temperature of the solvent or by irradiationin the microwave at a temperature between 100° C. and 160° C. to give acompound of structure 1A in which R¹ is a substituted alkyne and R² is aprotected amine (such as an acetamide or a trifluoroacetamide).Alternatively, a compound of structure 1A in which R¹ is an appropriategroup (such as a halogen, for example bromine or iodine, or a triflate)and R² is a protected amine (such as an acetamide or atrifluoroacetamide) may be coupled with an acetylenic stannane in thepresence of a palladium catalyst (such as palladium chloride dppf) in anappropriate solvent (such as dioxane, dimethoxyethane ortetrahydrofuran) at a temperature between room temperature and thereflux temperature of the solvent or alternatively by irradiation in themicrowave at a temperature between 100° C. and 160° C. to give acompound of structure 1A in which R¹ is an alkyne and R² is a protectedamine (such as an acetamide or a trifluoroacetamide).

In Scheme 1, Step (iii), a compound of structure 1A in which R¹ is anappropriately substituted alkyne and R² is a protected amine (such as anacetamide of a trifluoroacetamide) may be treated with a base (such aspotassium carbonate or sodium methoxide) in an appropriate solvent (suchas acetone, DMF or methanol) at a temperature between room temperatureand the reflux temperature of the solvent to give a compound ofstructure 1D in which X′ is NH. Alternatively, a compound of structure1A in which R¹ is an appropriately substituted alkyne and R² is aprotected amine (such as an acetamide of a trifluoroacetamide) may betreated with a palladium catalyst (such asbis-(triphenylphosphine)palladium chloride) in the presence of a base(such as triethylamine) and an appropriate catalyst (such as copper(I)iodide) in a solvent (such as dimethylformamide) at a temperaturebetween room temperature and the reflux temperature of the solvent togive a compound of structure 1D in which X′ is NH.

The general synthetic strategy to elaborate 1D is shown in Scheme 2.

In Scheme 2, compounds of structure 1D may be converted to a variety ofcompounds of structure 1E using reactions known to those skilled in theart. In some cases modifications to the groups R⁹ and R¹⁰ in 1D may berequired in order to be able to generate the require ring systems. Oneskilled in the art will recognize that it may be necessary for variousfunctional groups to be protected prior to reaction. Specific steps inthe synthetic procedures are described in more detail below.

In Scheme 2, Step (i), 1D in which R⁹ and R¹⁰ are both H and the bondbetween the carbon atoms is a double bond, may be treated with diethylzinc and di-iodomethane optionally in the presence of additionalreagents (such as trifluoroacetic acid or zinc iodide) in a solvent(such as 1,2-dichloroethane) at a temperature between −78° C. and roomtemperature to give compounds of structure 2A in which the B′ ring is acyclopropyl ring. Alternatively, compounds of structure 1D in which R⁹and R¹⁰ are both H and the bond between the carbon atoms is a doublebond, may be treated with trimethyl sulfoxonium iodide or trimethylsulphonium iodide in the presence of a base (such as sodium hydride) ina solvent (such as dimethyl sulfoxide) at a temperature between roomtemperature and 100° C. Alternatively, compounds of structure 1D inwhich R⁹ and R¹⁰ are both H and the bond between the carbon atoms is adouble bond, may be treated with diazomethane in the presence of acatalyst (such as palladium acetate) in a solvent such as diethyl etherat a temperature between 0° C. and room temperature.

Alternatively, compounds of structure 2A may be prepared in a two stepprocedure. For example, in Scheme 2, Step (ii), 1D in which R⁹ and R¹⁰are both H and the bond between the carbon atoms is a double bond, maybe treated with trimethylsilyl diazomethane in the presence of acatalyst (such as palladium acetate) in a solvent (such as diethylether) at a temperature between 0° C. and room temperature to give theintermediate 2A′ in which J is H and J′ is a trimethyl silyl group. InScheme 2, Step (iii), intermediates 2A′ in which J is H and J′ is atrimethyl silyl group may be converted to compounds of structure 2A bytreatment with a source of fluoride, (for example tetrabutyl ammoniumfluoride) in a solvent (such as tetrahydrofuran) at a temperaturebetween 0° C. and room temperature.

Alternatively in Scheme 2, Step (ii), 1D in which R⁹ and R¹⁰ are both Hand the bond between the carbon atoms is a double bond, may be treatedwith a haloform (such as chloroform or bromoform) in the presence of abase such as sodium hydroxide or potassium t-butoxide in the presence ofa catalyst (such as triethylbenzylammonium chloride or tetrabutylammonium bromide) in a mixture of water and a halogenated solvent (suchas dicloromethane or dichloroethane) or alternatively in excess of thehaloform at a temperature between room temperature and 80° C. to givethe intermediate 2A′ in which J and J′ are both chlorine or bromine. InScheme 2, Step (iii), the intermediates 2A′ in which J and J′ are bothchlorine or bromine may be converted to compounds of structure 2A bytreatment with a base (such as sodium methoxide or sodium t-butoxide) ina solvent (such as tetrahydrofuran) at a temperature between roomtemperature and the reflux temperature of the solvent. Alternatively,the intermediates 2A′ in which J and J′ are both chlorine or bromine maybe converted to compounds of structure 2A by reduction; for example, bytreatment with lithium aluminium hydride in a solvent (such astetrahydrofuran) at a temperature between 0° C. and the refluxtemperature of the solvent or alternatively, for example byhydrogenation using a catalyst (such as palladium on carbon) in asolvent (such as methanol or ethanol), optionally in the presence of abase (such as triethylamine) Alternatively, the intermediates 2A′ inwhich J and J′ are both chlorine or bromine may be converted tocompounds of structure 2A under radical conditions; for example, bytreatment with a tin hydride (such as tributyl tin hydride) optionallyin the presence of a radical initiator (such asazo-bis-isobutyronitrile) in a solvent (such as toluene) at atemperature between room temperature and the reflux temperature of thesolvent.

In Scheme 2, Step (iv), 1D in which X′ includes a carbonyl (for examplewhere X′ is —O—C(O)—) and R⁹ and R¹⁰ are both H and the bond between thecarbon atoms is a double bond, may be converted to the correspondingcompounds 2B by treatment with ethylene in a solvent (such asdichloromethane) under photochemical conditions.

Alternatively compounds of structure 2B may be prepared in a multi-stepprocedure. For example, in Scheme 2, Step (v), 1D in which both R⁹ andR¹⁰ are both H and the bond between the two carbon atoms is a doublebond may be treated with an acrylate (such as ethyl acrylate) in asolvent (such as acetonitrile) under photochemical conditions to give anintermediate 2B′ in which J″ is an ester group (such as an ethyl ester).The ester may be hydrolysed by, for example, treatment with sodiumhydroxide or lithium hydroxide in a solvent such as aqueous ethanol oraqueous dioxane at a temperature between room temperature and the refluxtemperature of the solvent to give an intermediate of structure 2B′ inwhich J″ is a carboxylic acid. In Scheme 2, Step (vi), the acid may beremoved for example by heating in, for example, quinoline optionally inthe presence of a catalyst (such as copper) to around 200° C.

In Scheme 2, Step (vii), 1D in which R¹⁰ is a hydroxyl and R⁹ is a groupCH₂OH may be treated with a sulfonyl chloride (such as 4-toluenesulfonylchloride or methanesulfonyl chloride) in the presence of a base (such astriethylamine), optionally in the presence of 4-dimethylaminopyridine,in a solvent (such as dichloromethane or toluene) at a temperaturebetween room temperature and the reflux temperature of the solvent. Theproduct may be treated with a base (such as triethylamine,diisopropylethylamine or sodium hydride) in an appropriate solvent (suchas dichloromethane, tetrahydrofuran or DMF) to give a compound ofstructure 2C.

In Scheme 2, Step (viii), 1D in which R⁹ is CH₂CH₂OH and R¹⁰ is CH₂OHmay be converted to compounds 2D. One of the hydroxyl groups may need tobe protected and the other is treated with a sulfonyl chloride (such as4-toluenesulfonyl chloride or methanesulfonyl chloride) in the presenceof a base (such as triethylamine) optionally in the presence of4-dimethylaminopyridine, in a solvent (such as dichloromethane ortoluene) at a temperature between room temperature and the refluxtemperature of the solvent. After deprotection of the remaining hydroxylgroup, the intermediate may be treated with a base (such astriethylamine, diisopropylethylamine or sodium hydride) in a solvent(such as dichloromethane, tetrahydrofuran or dimethylformamide at atemperature between room temperature and the reflux temperature of thesolvent to give a compound of structure 2D.

Alternatively, compounds of structure 2D may be prepared in a 2 stepprocedure. For example, in Scheme 2, Step (ix), 1D in which R⁹ isCH₂CO₂H and R¹⁰ is CH₂OH may be converted to compounds of structure 2D′.The carboxylic acid may be converted to an acid chloride (by treatmentwith, for example, thionyl chloride or oxalyl chloride, optionally inthe presence of a catalytic amount of DMF in a solvent such asdichloromethane or toluene) or to a mixed anhydride (for example bytreatment with 2,4,6-trichlorobenzoyl chloride in the presence of a basesuch as diisopropylethylamine) or to an activated ester (for example bytreatment with HATU in the presence of a base such asdiisopropylethylamine or pyridine, or treatment withdiisopropylcarbodiimide in the presence of HOBT). The acid chloride,mixed anhydride or activated ester may then be treated with a base (suchas triethylamine or pyridine), in a solvent (such dichloromethane ortoluene) to give the compound of structure 2D′. In Scheme 2, Step (x),compounds of structure 2D′ may be converted to compounds of structure 2Dby reduction, for example, by treatment with lithium aluminium hydride,sodium diisobutylaluminium hydride or borane-dimethyl sulfide complex,in an appropriate solvent (such as tetrahydrofuran) at a temperaturebetween −78° C. and room temperature.

In Scheme 2, Step (xi), 1D in which R⁹ is CH₂CH₂OH and R¹⁰ is a hydroxylmay be treated with a sulfonyl chloride (such as 4-toluenesulfonylchloride or methanesulfonyl chloride) in the presence of a base (such astriethylamine), optionally in the presence of 4-dimethylaminopyridine,in a solvent (such as dichloromethane or toluene) at a temperaturebetween room temperature and the reflux temperature of the solvent,followed by treatment with a base (such as triethylamine,diisopropylethylamine or sodium hydride) in an appropriate solvent (suchas dichloromethane, tetrahydrofuran or DMF) at a temperature betweenroom temperature and the reflux temperature of the solvent to give acompound of structure 2E.

Alternatively, compounds of structure 2E may be prepared in a 2 stepprocedure. In Scheme 2, Step (xii), 1D in which R⁹ is H and R¹⁰ is oxomay be converted to compounds of structure 2E′ by treatment withchloroacetaldehyde or bromoacetaldehyde in the presence of an aqueousbase (such as sodium bicarbonate or sodium hydroxide in water) at atemperature between 0° C. and room temperature, followed by treatmentwith an acid (such as concentrated sulfuric acid) in a mixture of waterand an organic solvent (such as ethyl acetate).

In Scheme 2, Step (xiii), compounds of structure 2E may be prepared fromcompounds of structure 2E′ by hydrogenation in the presence of a metalcatalyst (such as palladium or palladium hydroxide on a solid supportsuch as carbon) in a solvent (such as an ether, for exampletetrahydrofuran or dioxane, or an alcohol, such as methanol or ethanol),optionally in the presence of an acid (such as acetic acid). Dependingupon the nature of the linker X′, the bond between the two rings may bereduced or not to give either a tetrahydrofuran or a dihydrofuran. Forexample, if X′ is —N═C— then the B′ ring in 2E will be a dihydrofuranwhereas if X′ is —OCH₂— then the B′ ring will be a tetrahydrofuran.

In Scheme 1, Step (vii), compounds of general structure 1E may beconverted to compounds of General Formula I by the conversion of thegroup G′ to a carboxylic acid. If the group G′ is a carboxylic ester(such as a methyl, tert-butyl or benzyl ester) then a variety ofreagents and conditions can be used to convert 1E into a compound of theGeneral Formula I. For example, if G′ is a methyl, ethyl or benzylester, it may be converted to a carboxylic acid by treatment with aninorganic base (such as lithium hydroxide or sodium hydroxide) in asolvent (such as methanol, dioxane or water, or mixtures thereof) at atemperature between room temperature and the reflux temperature of thesolvent, or alternatively by microwave irradiation at 120-180° C. for 10minutes to 1 hour. Alternatively if G′ is a benzyl ester it may beconverted to a carboxylic acid by hydrogenation in the presence of acatalyst (such as palladium on a solid support such as carbon) in asolvent (such as dioxane or ethyl acetate). Alternatively if G′ is atert-butyl ester, it may be converted to a carboxylic acid by treatmentwith an acid (such as trifluoromethanesulfonic acid or hydrogenchloride) in a solvent (such as dichloromethane or dioxane).

Alternatively, if the group G′ is a nitrile, it may be converted into acarboxylic acid by treatment with aqueous acid (such as a mineral acid,for example hydrochloric acid) under appropriate conditions (such asheating, for example to reflux); or by treatment with aqueous base (suchas an aqueous hydroxide, for example aqueous sodium hydroxide) underappropriate conditions (such as heating, for example to reflux).

Alternatively, if the group G′ is an aldehyde (CHO) or a hydroxymethyl(CH₂OH) moiety then it may be converted into a carboxylic acid bytreatment with a suitable oxidising reagent (such as potassiumpermanganate or chromic acid).

The general synthetic strategy to modify the group G is depicted inScheme 3. The G group may be introduced and/or modified either before,during or after the assembly of the tricyclic ring system. Specificsteps used to assemble sulfonamide are described in more detail below.

In Scheme 3, the asterisks denote either the presence of the groups R¹and R² (as shown in Scheme 1) or the presence of the D′ and B′ rings, orintermediates towards the preparation of the rings (as shown in Schemes1 and 2).

In Scheme 3, Step (i), compounds of structure 3A in which G is a nitrogroup may be converted to compounds 3B by reduction, for example bycatalytic hydrogenation in the presence of a metal catalyst (such aspalladium on a solid support such as carbon) in a solvent (such as anether, for example tetrahydrofuran, or an alcohol, for example methanolor ethanol). Alternatively, compounds of structure 3A in which G is anitro group may be converted to compounds of structure 3B by chemicalreduction. For example, the reduction may be achieved using a metal ormetal salt (such as iron, zinc or tin (II) chloride) in the presence ofan acid (such as hydrochloric acid or acetic acid).

In Scheme 3, Step (i), compounds of structure 3A in which G is aprotected amino group may be converted to compounds of structure 3B byremoval of the protecting groups. Protecting groups for amino groups arewell known to those skilled in the art and methods for their removal areequally well known [for example, see Greene, Wuts, Protective Groups inOrganic Synthesis. 2nd Ed. (1999)]. For example, compounds of structure3A in which F is an amino group protected with one or two Boc groups maybe converted to compounds of structure 3B by treatment with an acid(such as trifluoroacetic acid, formic acid or hydrogen chloride) in asolvent (such as dichloromethane or dioxane).

Alternatively, in Scheme 3, Step (i), compounds of structure 3A in whichG is a pivaloyl protected aniline may be converted to compounds ofstructure 3B by treatment with an acid (such as concentrated sulfuricacid) in a solvent (such as methanol) at a temperature between roomtemperature and the reflux temperature of the solvent.

In Scheme 3, Step (ii), compounds of structure 3B may be converted tocompounds of structure 3C by treatment with an appropriate sulfonylchloride (such as a substituted or unsubstituted benzene sulfonylchloride) or an activated sulfonate ester (such as a pentafluorophenylsulfonate ester) in the presence of a suitable base (such as pyridine,diisopropylethylamine or cesium carbonate) in a suitable solvent (suchas dichloromethane or dimethylformamide) at a temperature between roomtemperature and the reflux temperature of the solvent.

Intermediates towards the preparation of compounds of Formula 1 or, forexample, General Formula 1 may require reduction of an aromatic ringsystem to give the saturated ring system required in the compounds ofFormula 1. This hydrogenation may be carried out by hydrogenation of theintermediates in the presence of a metal catalyst (for example palladiumor palladium hydroxide on a solid support, such as carbon) in a solvent(such as ethanol, ethyl acetate or dioxane) optionally in the presenceof an acid (such as acetic acid). The reduction of the aromatic ringsmay be carried out before the formation of the tricyclic ring system orafter it or at any stage during the synsthesis as will be recognized bythose skilled in the art.

Compounds of any of Formula I, Formula II or, for example, GeneralFormula I as depicted above, or any of the intermediates described inthe schemes above, can be further derivatised by using one or morestandard synthetic methods known to those skilled in the art. Suchmethods can involve substitution, oxidation or reduction reactions.These methods can also be used to obtain or modify compounds of GeneralFormula I or any preceding intermediates by modifying, introducing orremoving appropriate functional groups. Particular substitutionapproaches include alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulfonylation, nitration, formylation,hydrolysis and coupling procedures. These procedures can be used tointroduce a functional group onto the parent molecule (such as thenitration or sulfonylation of aromatic rings) or to couple two moleculestogether (for example to couple an amine to a carboxylic acid to affordan amide; or to form a carbon-carbon bond between two heterocycles). Forexample, alcohol or phenol groups can be converted to ether groups bycoupling a phenol with an alcohol in a solvent (such as tetrahydrofuran)in the presence of a phosphine (such as triphenylphosphine) and adehydrating agent (such as diethyl, diisopropyl or dimethylazodicarboxylate). Alternatively, ether groups can be prepared bydeprotonation of an alcohol, using a suitable base (such as sodiumhydride) followed by the addition of an alkylating agent (such as analkyl halide or an alkyl sulfonate).

In another example, a primary or secondary amine can be alkylated usinga reductive alkylation procedure. For example, the amine can be treatedwith an aldehyde and a borohydride (such as sodiumtriacetoxyborohydride, or sodium cyanoborohydride in a solvent (such asa halogenated hydrocarbon, for example dichloromethane, or an alcohol,for example ethanol) and, where necessary, in the presence of an acid(such as acetic acid).

In another example, hydroxy groups (including phenolic OH groups) can beconverted into leaving groups, such as halogen atoms or sulfonyloxygroups (such as alkylsulfonyloxy, for exampletrifluoromethanesulfonyloxy, or aryl suphonyloxy, for examplep-toluenesulfonyloxy) using conditions known to those skilled in theart. For example, an aliphatic alcohol can be reacted with thionylchloride in a halogenated hydrocarbon (such as dichloromethane) toafford the corresponding alkyl chloride. A base (such as triethylamine)can also be used in the reaction.

In another example, ester groups can be converted to the correspondingcarboxylic acid by acid- or base-catalysed hydrolysis depending on thenature of the ester group. Acid catalysed hydrolysis can be achieved bytreatment with an organic or inorganic acid (such as trifluoroaceticacid in an aqueous solvent, or a mineral acid such as hydrochloric acidin a solvent such as dioxane). Base catalysed hydrolysis can be achievedby treatment with an alkali metal hydroxide (such as lithium hydroxidein an aqueous alcohol, for example methanol).

In another example, aromatic halogen substituents in the compounds maybe subjected to halogen-metal exchange by treatment with a base (such asa lithium base, for example n-butyl or t-butyl lithium) optionally at alow temperature (such as −78° C.) in a solvent (such as tetrahydrofuran)and the mixture may then be quenched with an electrophile to introduce adesired substituent. Thus, for example, a formyl group can be introducedby using dimethylformamide as the electrophile. Aromatic halogensubstituents can also be subjected to palladium catalysed reactions tointroduce groups such as carboxylic acids, esters, cyano or aminosubstituents.

In another example, an aryl, or heteroaryl ring substituted with anappropriate leaving group (such as a halogen or sulfonyl ester, forexample a triflate) can undergo a palladium catalysed coupling reactionwith a wide variety of substrates to form a carbon-carbon bond. Forexample, a Heck reaction can be used to couple such a ring system to analkene (which may, or may not, be further substituted) by treatment withan organopalladium complex (such astetrakis(triphenylphosphine)palladium(0), palladium (II) acetate orpalladium (II) chloride) in the presence of a ligand (such as aphosphine, for example triphenylphosphine) in the presence of a base(such as potassium carbonate or a tertiary amine, for example,triethylamine), in an appropriate solvent (such as tetrahydrofuran orDMF), under appropriate conditions (such as heating to, for example,50-120° C.). In another example, a Sonogashira reaction can be used tocouple such a ring system to an alkyne (which may, or may not be furthersubstituted) by treatment with a palladium complex (such astetrakis(triphenylphosphine)palladium(0)) and a halide salt of copper(I) (such as copper (I) iodide), in the presence of a base (such as apotassium carbonate or a tertiary amine, for example, triethylamine), inan appropriate solvent (such as tetrahydrofuran or dimethylformamide),under appropriate conditions (such as heating to, for example, 50-120°C.). In another example, a Stille reaction can be used to couple such aring system to an alkene, by treatment with an organotin compound (suchas an alkynyltin or alkenyltin reagent, for example analkenyltributylstannane) in the presence of a palladium complex (such astetrakis(triphenylphosphine)palladium(0)), with, or without the presenceof a salt (such as a copper (I) halide), in an appropriate solvent (suchas dioxane or dimethylformamide), under appropriate conditions (such asheating to, for example, 50-120° C.).

Particular oxidation approaches include dehydrogenations andaromatisation, decarboxylation and the addition of oxygen to certainfunctional groups. For example, aldehyde groups can be prepared byoxidation of the corresponding alcohol using conditions well known tothose skilled in the art. For example, an alcohol can be treated with anoxidising agent (such as Dess-Martin periodinane) in a solvent (such asa halogenated hydrocarbon, for example dichloromethane). Alternativeoxidising conditions can be used, such as treatment with oxalyl chlorideand an activating amount of dimethylsulfoxide and subsequent quenchingby the addition of an amine (such as triethylamine) Such a reaction canbe carried out in an appropriate solvent (such as a halogenatedhydrocarbon, for example dichloromethane) and under appropriateconditions (such as cooling below room temperature, for example to −78°C. followed by warming to room temperature). In another example, sulfuratoms can be oxidised to the corresponding sulfoxide or sulfone using anoxidising agent (such as a peroxy acid, for example3-chloroperoxybenzoic acid) in an inert solvent (such as a halogenatedhydrocarbon, for example dichloromethane) at around ambient temperature.

Particular reduction approaches include the removal of oxygen atoms fromparticular functional groups or saturation (or partial saturation) ofunsaturated compounds including aromatic or heteroaromatic rings. Forexample, primary alcohols can be generated from the corresponding esteror aldehyde by reduction, using a metal hydride (such as lithiumaluminium hydride or sodium borohydride in a solvent such as methanol).Alternatively, CH₂OH groups can be generated from the correspondingcarboxylic acid by reduction, using a metal hydride (such as lithiumaluminium hydride in a solvent such as tetrahydrofuran). In anotherexample, a nitro group may be reduced to an amine by catalytichydrogenation in the presence of a metal catalyst (such as palladium ona solid support such as carbon) in a solvent (such as an ether, forexample tetrahydrofuran, or an alcohol, such as methanol), or bychemical reduction using a metal (such as zinc, tin or iron) in thepresence of an acid (such as acetic acid or hydrochloric acid). In afurther example an amine can be obtained by reduction of a nitrile, forexample by catalytic hydrogenation in the presence of a metal catalyst(such as palladium on a solid support such as carbon), or Raney nickelin a solvent (such as tetrahydrofuran) and under suitable conditions(such as cooling to below room temperature, for example to −78° C., orheating, for example to reflux).

Salts of compounds of General Formula I can be prepared by the reactionof a compound of General Formula I with an appropriate acid or base in asuitable solvent, or mixture of solvents (such as an ether, for example,diethyl ether, or an alcohol, for example ethanol, or an aqueoussolvent) using conventional procedures. Salts of compound of GeneralFormula I can be exchanged for other salts by treatment usingconventional ion-exchange chromatography procedures.

Where it is desired to obtain a particular enantiomer of a compound ofGeneral Formula I, this may be produced from a corresponding mixture ofenantiomers by employing any suitable conventional procedure forresolving enantiomers. For example, diastereomeric derivatives (such assalts) can be produced by reaction of a mixture of enantiomers of acompound of General Formula I (such a racemate) and an appropriatechiral compound (such as a chiral base). The diastereomers can then beseparated by any conventional means such as crystallisation, and thedesired enantiomer recovered (such as by treatment with an acid in theinstance where the diastereomer is a salt). Alternatively, a racemicmixture of esters can be resolved by kinetic hydrolysis using a varietyof biocatalysts (for example, see Patel Steroselective Biocatalysts,Marcel Decker; New York 2000).

In another resolution process a racemate of compounds of General FormulaI can be separated using chiral High Performance Liquid Chromatography.Alternatively, a particular enantiomer can be obtained by using anappropriate chiral intermediate in one of the processes described above.Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the invention.

II. Methods

Another aspect of the invention provides methods of modulating theactivity of MetAP2. Such methods comprise exposing said receptor to acompound described herein. In some embodiments, the compound utilized byone or more of the foregoing methods is one of the generic, subgeneric,or specific compounds described herein. The ability of compoundsdescribed herein to modulate or inhibit MetAP2 can be evaluated byprocedures known in the art and/or described herein. Another aspect ofthe invention provides methods of treating a disease associated withexpression or activity of MetAP2 in a patient. For example, acontemplated method includes administering a disclosed compound in anamount sufficient to establish inhibition of intracellular MetAP2effective to increase thioredoxin production in the patient and toinduce multi organ stimulation of anti-obesity processes in the subject,for example, by administering a disclosed compound in an amountinsufficient to reduce angiogenesis in the patient.

In certain embodiments, the invention provides a method of treating andor ameliorating obesity in a patient by administering an effectiveamount of a disclosed compound. Also provided herein are methods forinducing weight loss in a patient in need thereof. Contemplated patientsinclude not only humans, but other animals such as companion animals(e.g., dogs, cats).

Other contemplated methods of treatment include method of treating orameliorating an obesity-related condition or co-morbidity, byadministering a compound disclosed herein to a subject. For example,contemplated herein are methods for treating type 2 diabetes in apatient in need thereof

Exemplary co-morbidities include cardiac disorders, endocrine disorders,respiratory disorders, hepatic disorders, skeletal disorders,psychiatric disorders, metabolic disorders, and reproductive disorders.

Exemplary cardiac disorders include hypertension, dyslipidemia, ischemicheart disease, cardiomyopathy, cardiac infarction, stroke, venousthromboembolic disease and pulmonary hypertension. Exemplary endocrinedisorders include type 2 diabetes and latent autoimmune diabetes inadults. Exemplary respiratory disorders include obesity-hypoventilationsyndrome, asthma, and obstructive sleep apnea. An exemplary hepaticdisorder is nonalcoholic fatty liver disease. Exemplary skeletaldisorders include back pain and osteoarthritis of weight-bearing joints.Exemplary metabolic disorders include Prader-Willi Syndrome andpolycystic ovary syndrome. Exemplary reproductive disorders includesexual dysfunction, erectile dysfunction, infertility, obstetriccomplications, and fetal abnormalities. Exemplary psychiatric disordersinclude weight-associated depression and anxiety.

In particular, in certain embodiments, the invention provides a methodof treating the above medical indications comprising administering to asubject in need thereof a therapeutically effective amount of a compounddescribed herein.

Obesity or reference to “overweight” refers to an excess of fat inproportion to lean body mass. Excess fat accumulation is associated withincrease in size (hypertrophy) as well as number (hyperplasia) ofadipose tissue cells. Obesity is variously measured in terms of absoluteweight, weight:height ratio, distribution of subcutaneous fat, andsocietal and esthetic norms. A common measure of body fat is Body MassIndex (BMI). The BMI refers to the ratio of body weight (expressed inkilograms) to the square of height (expressed in meters). Body massindex may be accurately calculated using either of the formulas:weight(kg)/height²(m²) (SI) or 703× weight(lb)/height²(in²) (US).

In accordance with the U.S. Centers for Disease Control and Prevention(CDC), an overweight adult has a BMI of 25 kg/m² to 29.9 kg/m², and anobese adult has a BMI of 30 kg/m² or greater. A BMI of 40 kg/m² orgreater is indicative of morbid obesity or extreme obesity. Obesity canalso refer to patients with a waist circumference of about 102 cm formales and about 88 cm for females. For children, the definitions ofoverweight and obese take into account age and gender effects on bodyfat. Patients with differing genetic background may be considered“obese” at a level differing from the general guidelines, above.

The compounds of the present invention also are useful for reducing therisk of secondary outcomes of obesity, such as reducing the risk of leftventricular hypertrophy. Methods for treating patients at risk ofobesity, such as those patients who are overweight, but not obese, e.g.with a BMI of between about 25 and 30 kg/m², are also contemplated. Incertain embodiments, a patient is a human.

BMI does not account for the fact that excess adipose can occurselectively in different parts of the body, and development of adiposetissue can be more dangerous to health in some parts of the body ratherthan in other parts of the body. For example, “central obesity”,typically associated with an “apple-shaped” body, results from excessadiposity especially in the abdominal region, including belly fat andvisceral fat, and carries higher risk of co-morbidity than “peripheralobesity”, which is typically associated with a “pear-shaped” bodyresulting from excess adiposity especially on the hips. Measurement ofwaist/hip circumference ratio (WHR) can be used as an indicator ofcentral obesity. A minimum WHR indicative of central obesity has beenvariously set, and a centrally obese adult typically has a WHR of about0.85 or greater if female and about 0.9 or greater if male.

Methods of determining whether a subject is overweight or obese thataccount for the ratio of excess adipose tissue to lean body mass involveobtaining a body composition of the subject. Body composition can beobtained by measuring the thickness of subcutaneous fat in multipleplaces on the body, such as the abdominal area, the subscapular region,arms, buttocks and thighs. These measurements are then used to estimatetotal body fat with a margin of error of approximately four percentagepoints. Another method is bioelectrical impedance analysis (BIA), whichuses the resistance of electrical flow through the body to estimate bodyfat. Another method is using a large tank of water to measure bodybuoyancy. Increased body fat will result in greater buoyancy, whilegreater muscle mass will result in a tendency to sink.

In another aspect, the invention provides methods for treating anoverweight or obese subject involving determining a level of at leastone biomarker related to being overweight or obese in the subject, andadministering an effective amount of a disclosed compound to achieve atarget level in the subject. Exemplary biomarkers include body weight,Body Mass Index (BMI), Waist/Hip ratio WHR, plasma adipokines, and acombination of two or more thereof

In certain embodiments, the compound utilized by one or more of theforegoing methods is one of the generic, subgeneric, or specificcompounds described herein.

The compounds of the invention may be administered to patients (animalsand humans) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. It will be appreciated that the doserequired for use in any particular application will vary from patient topatient, not only with the particular compound or composition selected,but also with the route of administration, the nature of the conditionbeing treated, the age and condition of the patient, concurrentmedication or special diets then being followed by the patient, andother factors which those skilled in the art will recognize, with theappropriate dosage ultimately being at the discretion of the attendantphysician. For treating clinical conditions and diseases noted above, acompound of this invention may be administered orally, subcutaneously,topically, parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Parenteral administrationmay include subcutaneous injections, intravenous or intramuscularinjections or infusion techniques.

Treatment can be continued for as long or as short a period as desired.The compositions may be administered on a regimen of, for example, oneto four or more times per day. A suitable treatment period can be, forexample, at least about one week, at least about two weeks, at leastabout one month, at least about six months, at least about 1 year, orindefinitely. A treatment period can terminate when a desired result,for example a weight loss target, is achieved. A treatment regimen caninclude a corrective phase, during which dose sufficient to providereduction of weight is administered, and can be followed by amaintenance phase, during which a e.g. a lower dose sufficient toprevent weight gain is administered. A suitable maintenance dose islikely to be found in the lower parts of the dose ranges providedherein, but corrective and maintenance doses can readily be establishedfor individual subjects by those of skill in the art without undueexperimentation, based on the disclosure herein. Maintenance doses canbe employed to maintain body weight in subjects whose body weight hasbeen previously controlled by other means, including diet and exercise,bariatric procedures such as bypass or banding surgeries, or treatmentsemploying other pharmacological agents.

III. Pharmaceutical Compositions and Kits

Another aspect of the invention provides pharmaceutical compositionscomprising compounds as disclosed herein formulated together with apharmaceutically acceptable carrier. In particular, the presentdisclosure provides pharmaceutical compositions comprising compounds asdisclosed herein formulated together with one or more pharmaceuticallyacceptable carriers. These formulations include those suitable for oral,rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous) rectal, vaginal, or aerosol administration,although the most suitable form of administration in any given case willdepend on the degree and severity of the condition being treated and onthe nature of the particular compound being used. For example, disclosedcompositions may be formulated as a unit dose, and/or may be formulatedfor oral or subcutaneous administration.

Exemplary pharmaceutical compositions of this invention may be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains one or more of the compound ofthe invention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The active objectcompound is included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or conditionof the disease.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof and (10) coloring agents. Inthe case of capsules, tablets and pills, the compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions, in addition to the subject composition, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and release theactive agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compositions and compounds of the present invention may alternatively beadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. A non-aqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers may be used because they minimize exposing theagent to shear, which may result in degradation of the compoundscontained in the subject compositions. Ordinarily, an aqueous aerosol ismade by formulating an aqueous solution or suspension of a subjectcomposition together with conventional pharmaceutically acceptablecarriers and stabilizers. The carriers and stabilizers vary with therequirements of the particular subject composition, but typicallyinclude non-ionic surfactants (Tweens, Pluronics, or polyethyleneglycol), innocuous proteins like serum albumin, sorbitan esters, oleicacid, lecithin, amino acids such as glycine, buffers, salts, sugars orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise a subject composition in combination with one ormore pharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate and cyclodextrins. Proper fluidity may be maintained,for example, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants

In another aspect, the invention provides enteral pharmaceuticalformulations including a disclosed compound and an enteric material; anda pharmaceutically acceptable carrier or excipient thereof. Entericmaterials refer to polymers that are substantially insoluble in theacidic environment of the stomach, and that are predominantly soluble inintestinal fluids at specific pHs. The small intestine is the part ofthe gastrointestinal tract (gut) between the stomach and the largeintestine, and includes the duodenum, jejunum, and ileum. The pH of theduodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH ofthe distal ileum is about 7.5. Accordingly, enteric materials are notsoluble, for example, until a pH of about 5.0, of about 5.2, of about5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary entericmaterials include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP),hydroxypropyl methylcellulose acetate succinate (HPMCAS), celluloseacetate trimellitate, hydroxypropyl methylcellulose succinate, celluloseacetate succinate, cellulose acetate hexahydrophthalate, cellulosepropionate phthalate, cellulose acetate maleate, cellulose acetatebutyrate, cellulose acetate propionate, copolymer of methylmethacrylicacid and methyl methacrylate, copolymer of methyl acrylate,methylmethacrylate and methacrylic acid, copolymer of methylvinyl etherand maleic anhydride (Gantrez ES series), ethylmethyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e.g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, KollicoatEMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of eachof the above materials is either known or is readily determinable invitro. The foregoing is a list of possible materials, but one of skillin the art with the benefit of the disclosure would recognize that it isnot comprehensive and that there are other enteric materials that wouldmeet the objectives of the present invention.

Advantageously, the invention also provides kits for use by a e.g. aconsumer in need of weight loss. Such kits include a suitable dosageform such as those described above and instructions describing themethod of using such dosage form to mediate, reduce or preventinflammation. The instructions would direct the consumer or medicalpersonnel to administer the dosage form according to administrationmodes known to those skilled in the art. Such kits could advantageouslybe packaged and sold in single or multiple kit units. An example of sucha kit is a so-called blister pack. Blister packs are well known in thepackaging industry and are being widely used for the packaging ofpharmaceutical unit dosage forms (tablets, capsules, and the like).Blister packs generally consist of a sheet of relatively stiff materialcovered with a foil of a preferably transparent plastic material. Duringthe packaging process recesses are formed in the plastic foil. Therecesses have the size and shape of the tablets or capsules to bepacked. Next, the tablets or capsules are placed in the recesses and thesheet of relatively stiff material is sealed against the plastic foil atthe face of the foil which is opposite from the direction in which therecesses were formed. As a result, the tablets or capsules are sealed inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a first compound can consistof one tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

Also contemplated herein are methods and compositions that include asecond active agent, or administering a second active agent. Forexample, in addition to being overweight or obese, a subject or patientcan further have overweight- or obesity-related co-morbidities, i.e.,diseases and other adverse health conditions associated with,exacerbated by, or precipitated by being overweight or obese.Contemplated herein are disclosed compounds in combination with at leastone other agent that has previously been shown to treat theseoverweight- or obesity-related conditions.

For example, Type II diabetes has been associated with obesity. Certaincomplications of Type II diabetes, e.g., disability and premature death,can be prevented, ameliorated, or eliminated by sustained weight loss(Astrup, A. Pub Health Nutr (2001) 4:499-5 15). Agents administered totreat Type II diabetes include sulfonylureas (e.g., Chlorpropamide,Glipizide, Glyburide, Glimepiride); meglitinides (e.g., Repaglinide andNateglinide); biguanides (e.g., Metformin); thiazolidinediones(Rosiglitazone, Troglitazone, and Pioglitazone); dipeptidylpeptidase-4inhibitors (e.g., Sitagliptin, Vildagliptin, and Saxagliptin);glucagon-like peptide-1 mimetics (e.g., Exenatide and Liraglutide); andalpha-glucosidase inhibitors (e.g., Acarbose and Miglitol.

Cardiac disorders and conditions, for example hypertension,dyslipidemia, ischemic heart disease, cardiomyopathy, cardiacinfarction, stroke, venous thromboembolic disease and pulmonaryhypertension, have been linked to overweight or obesity. For example,hypertension has been linked to obesity because excess adipose tissuesecretes substances that are acted on by the kidneys, resulting inhypertension. Additionally, with obesity there are generally higheramounts of insulin produced (because of the excess adipose tissue) andthis excess insulin also elevates blood pressure. A major treatmentoption of hypertension is weight loss. Agents administered to treathypertension include Chlorthalidone; Hydrochlorothiazide; Indapamide,Metolazone; loop diuretics (e.g., Bumetanide, Ethacrynic acid,Furosemide, Lasix, Torsemide); potassium-sparing agents (e.g., Amiloridehydrochloride, benzamil, Spironolactone, and Triamterene); peripheralagents (e.g., Reserpine); central alpha-agonists (e.g., Clonidinehydrochloride, Guanabenz acetate, Guanfacine hydrochloride, andMethyldopa); alpha-blockers (e.g., Doxazosin mesylate, Prazosinhydrochloride, and Terazosin hydrochloride); beta-blockers (e.g.,Acebutolol, Atenolol, Betaxolol, Bisoprolol fumarate, Carteololhydrochloride, Metoprolol tartrate, Metoprolol succinate, Nadolol,Penbutolol sulfate, Pindolol, Propranolol hydrochloride, and Timololmaleate); combined alpha- and beta-blockers (e.g., Carvedilol andLabetalol hydrochloride); direct vasodilators (e.g., Hydralazinehydrochloride and Minoxidil); calcium antagonists (e.g., Diltiazemhydrochloride and Verapamil hydrochloride); dihydropyridines (e.g.,Amlodipine besylate, Felodipine, Isradipine, Nicardipine, Nifedipine,and Nisoldipine); ACE inhibitors (benazepril hydrochloride, Captopril,Enalapril maleate, Fosinopril sodium, Lisinopril, Moexipril, Quinaprilhydrochloride, Ramipril, Trandolapril); Angiotensin II receptor blockers(e.g., Losartan potassium, Valsartan, and Irbesartan); Renin inhibitors(e.g., Aliskiren); and combinations thereof. These compounds areadministered in regimens and at dosages known in the art.

Carr et al. (The Journal of Clinical Endocrinology & Metabolism (2004)Vol. 89, No. 6 2601-2607) discusses a link between being overweight orobese and dyslipidemia. Dyslipidemia is typically treated with statins.Statins, HMG-CoA reductase inhibitors, slow down production ofcholesterol in a subject and/or remove cholesterol buildup fromarteries. Statins include mevastatin, lovastatin, pravastatin,simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin,dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin,rosuvastatin, pitavastatin, and glenvastatin. These compounds areadministered in regimens and at dosages known in the art. Eckel(Circulation (1997) 96:3248-3250) discusses a link between beingoverweight or obese and ischemic heart disease. Agents administered totreat ischemic heart disease include statins, nitrates (e.g., IsosorbideDinitrate and Isosorbide Mononitrate), beta-blockers, and calciumchannel antagonists. These compounds are administered in regimens and atdosages known in the art.

Wong et al. (Nature Clinical Practice Cardiovascular Medicine (2007)4:436-443) discusses a link between being overweight or obese andcardiomyopathy. Agents administered to treat cardiomyopathy includeinotropic agents (e.g., Digoxin), diuretics (e.g., Furosemide), ACEinhibitors, calcium antagonists, anti-arrhythmic agents (e.g., Sotolol,Amiodarone and Disopyramide), and beta-blockers. These compounds areadministered in regimens and at dosages known in the art. Yusef et al.(Lancet (2005) 366(9497):1640-1649) discusses a link between beingoverweight or obese and cardiac infarction. Agents administered to treatcardiac infarction include ACE inhibitors, Angiotensin II receptorblockers, direct vasodilators, beta blockers, anti-arrhythmic agents andthrombolytic agents (e.g., Alteplase, Retaplase, Tenecteplase,Anistreplase, and Urokinase). These compounds are administered inregimens and at dosages known in the art.

Suk et al. (Stroke (2003) 34:1586-1592) discusses a link between beingoverweight or obese and strokes. Agents administered to treat strokesinclude anti-platelet agents (e.g., Aspirin, Clopidogrel, Dipyridamole,and Ticlopidine), anticoagulant agents (e.g., Heparin), and thrombolyticagents. Stein et al. (The American Journal of Medicine (2005)18(9):978-980) discusses a link between being overweight or obese andvenous thromboembolic disease. Agents administered to treat venousthromboembolic disease include anti-platelet agents, anticoagulantagents, and thrombolytic agents. Sztrymf et al. (Rev Pneumol Clin (2002)58(2):104-10) discusses a link between being overweight or obese andpulmonary hypertension. Agents administered to treat pulmonaryhypertension include inotropic agents, anticoagulant agents, diuretics,potassium (e.g., K-dur), vasodilators (e.g., Nifedipine and Diltiazem),Bosentan, Epoprostenol, and Sildenafil. Respiratory disorders andconditions such as obesity-hypoventilation syndrome, asthma, andobstructive sleep apnea, have been linked to being overweight or obese.Elamin (Chest (2004) 125:1972-1974) discusses a link between beingoverweight or obese and asthma. Agents administered to treat asthmainclude bronchodilators, anti-inflammatory agents, leukotriene blockers,and anti-Ige agents. Particular asthma agents include Zafirlukast,Flunisolide, Triamcinolone, Beclomethasone, Terbutaline, Fluticasone,Formoterol, Beclomethasone, Salmeterol, Theophylline, and Xopenex.

Kessler et al. (Eur Respir J (1996) 9:787-794) discusses a link betweenbeing overweight or obese and obstructive sleep apnea. Agentsadministered to treat sleep apnea include Modafinil and amphetamines.

Hepatic disorders and conditions, such as nonalcoholic fatty liverdisease, have been linked to being overweight or obese. Tolman et al.(Ther Clin Risk Manag (2007) 6:1153-1163) discusses a link between beingoverweight or obese and nonalcoholic fatty liver disease. Agentsadministered to treat nonalcoholic fatty liver disease includeantioxidants (e.g., Vitamins E and C), insulin sensitizers (Metformin,Pioglitazone, Rosiglitazone, and Betaine), hepatoprotectants, andlipid-lowering agents.

Skeletal disorders and conditions, such as, back pain and osteoarthritisof weight-bearing joints, have been linked to being overweight or obese.van Saase (J Rheumatol (1988) 15(7):1152-1158) discusses a link betweenbeing overweight or obese and osteoarthritis of weight-bearing joints.Agents administered to treat osteoarthritis of weight-bearing jointsinclude Acetaminophen, non-steroidal anti-inflammatory agents (e.g.,Ibuprofen, Etodolac, Oxaprozin, Naproxen, Diclofenac, and Nabumetone),COX-2 inhibitors (e.g., Celecoxib), steroids, supplements (e.g.glucosamine and chondroitin sulfate), and artificial joint fluid.

Metabolic disorders and conditions, for example, Prader-Willi Syndromeand polycystic ovary syndrome, have been linked to being overweight orobese. Cassidy (Journal of Medical Genetics (1997) 34:917-923) discussesa link between being overweight or obese and Prader-Willi Syndrome.Agents administered to treat Prader-Willi Syndrome include human growthhormone (HGH), somatropin, and weight loss agents (e.g., Orlistat,Sibutramine, Methamphetamine, Ionamin, Phentermine, Bupropion,Diethylpropion, Phendimetrazine, Benzphetermine, and Topamax).

Hoeger (Obstetrics and Gynecology Clinics of North America (2001)28(1):85-97) discusses a link between being overweight or obese andpolycystic ovary syndrome. Agents administered to treat polycystic ovarysyndrome include insulin-sensitizers, combinations of synthetic estrogenand progesterone, Spironolactone, Eflornithine, and Clomiphene.Reproductive disorders and conditions such as sexual dysfunction,erectile dysfunction, infertility, obstetric complications, and fetalabnormalities, have been linked to being overweight or obese. Larsen etal. (Int J Obes (Lond) (2007) 8:1189-1198) discusses a link betweenbeing overweight or obese and sexual dysfunction. Chung et al. (Eur Urol(1999) 36(1):68-70) discusses a link between being overweight or obeseand erectile dysfunction. Agents administered to treat erectiledysfunction include phosphodiesterase inhibitors (e.g., Tadalafil,Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g.,Alprostadil), alkaloids (e.g., Yohimbine), and testosterone. Pasquali etal. (Hum Reprod (1997) 1:82-87) discusses a link between beingoverweight or obese and infertility. Agents administered to treatinfertility include Clomiphene, Clomiphene citrate, Bromocriptine,Gonadotropin-releasing Hormone (GnRH), GnRH agonist, GnRH antagonist,Tamoxifen/nolvadex, gonadotropins, Human Chorionic Gonadotropin (HCG),Human Menopausal Gonadotropin (HmG), progesterone, recombinant folliclestimulating hormone (FSH), Urofollitropin, Heparin, Follitropin alfa,and Follitropin beta.

Weiss et al. (American Journal of Obstetrics and Gynecology (2004)190(4):1091-1097) discusses a link between being overweight or obese andobstetric complications. Agents administered to treat obstetriccomplications include Bupivacaine hydrochloride, Dinoprostone PGE2,Meperidine HCl, Ferro-folic-500/iberet-folic-500, Meperidine,Methylergonovine maleate, Ropivacaine HCl, Nalbuphine HCl, OxymorphoneHCl, Oxytocin, Dinoprostone, Ritodrine, Scopolamine hydrobromide,Sufentanil citrate, and Oxytocic.

Psychiatric disorders and conditions, for example, weight-associateddepression and anxiety, have been linked to being overweight or obese.Dixson et al. (Arch Intern Med (2003) 163:2058-2065) discusses a linkbetween being overweight or obese and depression. Agents administered totreat depression include serotonin reuptake inhibitors (e.g.,Fluoxetine, Escitalopram, Citalopram, Paroxetine, Sertraline, andVenlafaxine); tricyclic antidepressants (e.g., Amitriptyline, Amoxapine,Clomipramine, Desipramine, Dosulepin hydrochloride, Doxepin, Imipramine,Iprindole, Lofepramine, Nortriptyline, Opipramol, Protriptyline, andTrimipramine); monoamine oxidase inhibitors (e.g., Isocarboxazid,Moclobemide, Phenelzine, Tranylcypromine, Selegiline, Rasagiline,Nialamide, Iproniazid, Iproclozide, Toloxatone, Linezolid, Dienolidekavapyrone desmethoxyyangonin, and Dextroamphetamine); psychostimulants(e.g., Amphetamine, Methamphetamine, Methylphenidate, and Arecoline);antipsychotics (e.g., Butyrophenones, Phenothiazines, Thioxanthenes,Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone,Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); andmood stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproexsodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin,Oxcarbazepine, and Topiramate).

Simon et al. (Archives of General Psychiatry (2006) 63(7):824-830)discusses a link between being overweight or obese and anxiety. Agentsadministered to treat anxiety include serotonin reuptake inhibitors,mood stabilizers, benzodiazepines (e.g., Alprazolam, Clonazepam,Diazepam, and Lorazepam), tricyclic antidepressants, monoamine oxidaseinhibitors, and beta-blockers.

Another aspect of the invention provides methods for facilitating andmaintaining weight loss in a subject involving administering to thesubject an amount of a disclosed compound effective to result in weightloss in the subject; and administering a therapeutically effectiveamount of a different weight loss agent to maintain a reduced weight inthe subject. Weight loss agents include serotonin and noradrenergicre-uptake inhibitors; noradrenergic re-uptake inhibitors; selectiveserotonin re-uptake inhibitors; and intestinal lipase inhibitors.Particular weight loss agents include orlistat, sibutramine,methamphetamine, ionamin, phentermine, bupropion, diethylpropion,phendimetrazine, benzphetermine, bromocriptine, lorcaserin, topiramate,or agents acting to modulate food intake by blocking ghrelin action,inhibiting diacylglycerol acyltransferase 1 (DGAT1) activity, inhibitingstearoyl CoA desaturase 1 (SCD1) activity, inhibiting neuropeptide Yreceptor 1 function, activating neuropeptide Y receptor 2 or 4 function,or inhibiting activity of sodium-glucose cotransporters 1 or 2. Thesecompounds are administered in regimens and at dosages known in the art.

EXAMPLES

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein arecontemplated as compounds of the invention.

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz) spectrometer with a triple resonance 5 mm probe forExample compounds, and either a Bruker Avance DRX (400 MHz) spectrometeror a Bruker Avance DPX (300 MHz) spectrometer for Intermediatecompounds. Chemical shifts are expressed in ppm relative totetramethylsilane. The following abbreviations have been used: br=broadsignal, s=singlet, d=doublet, dd=double doublet, ddd=double doubledoublet, dt=double triplet, t=triplet, td=triple doublet, q=quartet,m=multiplet.

Mass Spectrometry (LCMS) experiments to determine retention times andassociated mass ions were performed using the following methods:

Method A: Experiments were performed on a Waters ZMD LC quadruple massspectrometer linked to a Waters 1525 LC system with a diode arraydetector. The spectrometer has an electrospray source operating inpositive and negative ion mode. Additional detection was achieved usinga Sedex 85 evaporative light scattering detector. LC was carried outusing a Luna 3 micron 30×4.6 mm C18 column and a 2 mL/minute flow rate.The initial solvent system was 95% water containing 0.1% formic acid(solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B)for the first 0.5 minute followed by a gradient up to 5% solvent A and95% solvent B over the next 4 minutes. The final solvent system was heldconstant for a further 1 minute.

Method B: Experiments were performed on a Waters V G Platform quadrupolespectrometer linked to a Hewlett Packard 1050 LC system with a diodearray detector. The spectrometer has an electrospray source operating inpositive and negative ion mode. Additional detection was achieved usinga Sedex 85 evaporative light scattering detector. LC was carried outusing a Luna 3 micron 30×4.6 mm C18 column and a 2 mL/minute flow rate.The initial solvent system was 95% water containing 0.1% formic acid(solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B)for the first 0.3 minute followed by a gradient up to 5% solvent A and95% solvent B over the next 4 minutes. The final solvent system was heldconstant for a further 1 minute.

Method C: Experiments were performed on a Waters Micromass ZQ2000quadruple mass spectrometer linked to a Waters Acquity UPLC system witha PDA UV detector. The spectrometer has an electrospray source operatingin positive and negative ion mode. LC was carried out using an AcquityBEH 1.7 micron C18 column, an Acquity BEH Shield 1.7 micron RP18 columnor an Acquity HSST 1.8 micron column. Each column has dimensions of100×2.1 mm and was maintained at 40° C. with a flow rate of 0.4mL/minute. The initial solvent system was 95% water containing 0.1%formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid(solvent B) for the first 0.4 minute followed by a gradient up to 5%solvent A and 95% solvent B over the next 6 minutes. The final solventsystem was held constant for a further 0.8 minutes.

Method D: Experiments were performed on a Waters ZMD LC quadruple massspectrometer linked to a Hewlett Packard HD 1100 system with a diodearray detector. The spectrometer has an electrospray source operating inpositive and negative ion mode. LC was carried out using a Luna 3 micron30×4.6 mm C18 column and a 2 mL/minute flow rate. The initial solventsystem was 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5minute followed by a gradient up to 5% solvent A and 95% solvent B overthe next 4 minutes. The final solvent system was held constant for afurther 1 minute.

Method E: Experiments were performed on a Waters Platform LC quadrupolemass spectrometer linked to a Hewlett Packard HP1100 LC system withdiode array detector and 100 position autosampler. The spectrometer hasan electrospray source operating in positive and negative ion mode.Additional detection was achieved using a Sedex 85 evaporative lightscattering detector. LC was carried out using a Phenomenex Luna 3 micron30×4.6 mm C18 column and a 2 mL/minute flow rate. The initial solventsystem was 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5minute followed by a gradient up to 5% solvent A and 95% solvent B overthe next 4 minutes. The final solvent system was held constant for afurther 1 minute.

Method F: Experiments were performed on a Waters ZQ quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system withquaternary pump and PDA detector. The spectrometer has an electrospraysource operating in positive and negative ion mode. Additional detectionwas achieved using a Sedex 65 evaporative light scattering detector. LCwas carried out using a Phenomenex Luna 3 micron 30×4.6 mm C18 columnand a 2 mL/minute flow rate. The initial solvent system was 95% watercontaining 0.1% formic acid (solvent A) and 5% acetonitrile containing0.1% formic acid (solvent B) for the first 0.3 minute followed by agradient up to 5% solvent A and 95% solvent B over the next 4 minutes.The final solvent system was held constant for a further 1 minute.

Microwave experiments were carried out using a Biotage Initiator™, whichuses a single-mode resonator and dynamic field tuning. Temperatures from40-250° C. can be achieved, and pressures of up to 20 bars can bereached. A facility exists to apply air cooling during the irradiation.

Preparative HPLC purification was carried out using either aC18-reverse-phase column from Genesis (C18) or a C6-phenyl column fromPhenomenex (C6-phenyl) (100×22.5 mm i d with 7 micron particle size, UVdetection at 230 or 254 nm, flow 5-15 mL/min), eluting with gradientsfrom 100-0 to 0-100% water/acetonitrile or water/methanol containing0.1% formic acid. Fractions containing the required product (identifiedby LCMS analysis) were pooled, the organic fraction removed byevaporation, and the remaining aqueous fraction lyophilised, to give theproduct.

Alternatively, preparative HPLC purification was carried out using anmass directed automated purification system (MDAP) using an Agilent 1260infinity purifications system with an Agilent 6100 series singleQuadrupole LC/MS. The column used was an X-Select C18 CSH 5 μm, 30×150mm. Chromatography was carried out using gradients from 10-95%water/acetonitrile containing 0.1% formic acid centered around a focusedgradient.

Compounds which required column chromatography were purified manually orfully automatically using either a Biotage SP1™ Flash Purificationsystem with Touch Logic Control™ or a Combiflash Companion® withpre-packed silica gel Isolute® SPE cartridge, Biotage SNAP cartridge orRedisep® Rf cartridge respectively.

Compounds have been named using Autonom2000 within ISISDraw.

Abbreviations:

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCE 1,2-Dichloroethane

DCM Dichloromethane

DIBAL Diisobutylaluminium hydride

DMAP 4-Dimethylaminopyridine

DME Dimethoxymethane

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EDAC N-(3-Dimethylaminopropyl)-N′ethylcarbodiimide

Hydrochloride

HOBT 1-Hydroxybenzotriazole

IMS Industrial methylated spirits

SCX Strong cation exchange cartridge

TBME Methyl tert-butyl ether

TFA Trifluoroacetic acid

THF Tetrahydrofuran

Example 1

(1aR,7bS)-5-[2-(2-Diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Lithium hydroxide (0.052 g) was added to a solution of methyl(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(Intermediate 1, 0.062 g) in a mixture of dioxane (3 mL) and water (1mL) and the resultant mixture was irradiated in the microwave at 150° C.with air cooling for 20 minutes. After cooling, the solution wasacidified by addition of aqueous citric acid solution (10%) and theresultant mixture was extracted with DCM, dried (Na₂SO₄) and filtered.The filtrate was evaporated to dryness and the residue was purified bypreparative HPLC (C18) eluting with a mixture of acetonitrile and water,containing 0.1% formic acid, with a gradient of 20-98% to afford(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid (0.041 g) as a white solid.

¹H NMR (CDCl₃) δ: 8.11-8.03 (1H, m), 7.11-7.06 (1H, m), 7.04-6.94 (2H,m), 6.84 (1H, td), 4.41 (1H, dd), 3.83 (1H, d), 3.23-2.94 (6H, m),2.15-2.05 (1H, m), 1.92-1.85 (1H, m), 1.84-1.74 (1H, m), 1.74-1.65 (1H,m), 1.51-1.41 (1H, m), 1.26-1.16 (7H, m), 1.07-0.92 (2H, m).

LCMS (Method C) r/t 3.23 (M−H) 487.

Examples 2 and 3

Separation of enantiomers from Example 1.

Sample from Example 1 was subjected to chiral separation using aChiralPak IA column, 10 mm×250 mm, particle size 5 micron. Elutingsolvent: 55% heptane, 27% Ethanol and 18% DCM.

Example 2

First eluting enantiomer: r/t on analytical column (4.6 mm×250 mm):12.73 minutes as a white solid.

¹H NMR (DMSO-d₆) δ: 8.03 (1H, dd), 7.23 (1H, td), 7.17 (1H, d), 7.03(1H, d), 6.70 (1H, d), 4.23 (1H, d), 3.64 (1H, d), 3.07-2.96 (3H, m),2.95-2.86 (2H, m), 2.32-2.21 (1H, m), 1.93-1.85 (1H, m), 1.77-1.59 (2H,m), 1.49-1.41 (1H, m), 1.37-1.18 (2H, m), 1.01 (6H, t), 0.95-0.88 (1H,m), 0.71-0.65 (1H, m).

LCMS (Method C) r/t 3.25 (M−H) 487.

Example 3

Second eluting enantiomer: r/t on analytical column (4.6 mm×250 mm):22.3 minutes as a beige solid which was triturated with ether plus fewdrops of acetonitrile to give a white solid.

¹H NMR (DMSO-d₆) δ: 8.01 (1H, dd), 7.26-7.12 (2H, m), 7.01 (1H, d), 6.70(1H, d), 4.22 (1H, d), 3.63 (1H, d), 3.07-2.84 (5H, m), 2.34-2.23 (1H,m), 1.91-1.81 (1H, m), 1.76-1.60 (2H, m), 1.46-1.37 (1H, m), 1.31-1.19(2H, m), 1.01 (6H, t), 0.95-0.86 (1H, m), 0.75-0.70 (1H, m).

LCMS (Method C) r/t 3.23 (M+H) 489.

Example 4

(1aR,7bS)-5-{4-Fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 1, starting frommethyl(1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 14), as a white solid.

¹H NMR (CDCl₃) δ: 8.02-7.92 (1H, m), 7.14-7.07 (1H, m), 7.02-6.91 (2H,m), 6.77 (1H, ddd), 4.40 (1H, d), 3.82 (1H, dd), 3.36-3.02 (6H, m),2.34-2.24 (1H, m), 2.08-1.97 (4H, m), 1.94-1.76 (2H, m), 1.74-1.65 (1H,m), 1.48-1.37 (1H, m), 1.21-1.09 (1H, m), 1.07-0.91 (2H, m).

LCMS (Method C) r/t 3.21 (M−H) 485.

Example 5

(1aR,7bS)-5-[2-(3-Diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

A mixture of methyl(1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 15, 0.133 g) and lithium hydroxide monohydrate (0.168 g)in water (1 mL) and dioxane (3 mL) was irradiated in the microwave at130° C. for 40 minutes. After cooling, the mixture was diluted withmethanol and acidified by addition of formic acid (10%). The volatileswere removed by evaporation and the residue was triturated with 15%methanol in DCM. The solid was filtered off and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography onsilica, eluting with a mixture of methanol and DCM with a gradient of0-30% to give(1aR,7bS)-5-{2-[3-(diethylamino)-2,2-dimethylpropyl]-4-fluorophenyl}sulfonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid (0.091 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 7.97-7.91 (1H, m), 7.20-7.12 (2H, m), 7.01 (1H, d),6.61 (1H, d), 4.21 (1H, d), 3.63 (1H, d), 3.04 (2H, s), 2.90-2.77 (4H,m), 2.65 (2H, br s), 1.90-1.82 (1H, m), 1.75-1.66 (1H, m), 1.08 (6H, t),0.97-0.86 (7H, m), 0.76-0.70 (1H, m).

LCMS (Method C) r/t 3.34 (M−H) 503.

Example 6

(1aR,7bS)-5-[4-Fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 5, starting frommethyl(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(Intermediate 21), as a white solid.

¹H NMR (DMSO-d₆) δ: 7.80 (1H, dd), 7.27 (1H, dd), 7.17-7.11 (1H, m),7.08 (1H, d), 7.00 (1H, d), 4.15 (1H, d), 3.61 (1H, d), 3.57-3.46 (1H,m), 3.25-2.87 (6H, m), 2.19-2.03 (1H, m), 1.93-1.85 (1H, m), 1.84-1.65(2H, m), 0.95-0.86 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.05 (M−H) 445.

Example 7

(1aR,7bS)-5-[4-Fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 5, starting frommethyl(1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(Intermediate 27), as a white solid.

¹H NMR (DMSO-d₆) δ: 7.80 (1H, dd), 7.27 (1H, dd), 7.17-7.11 (1H, m),7.08 (1H, d), 7.00 (1H, d), 4.15 (1H, d), 3.60-3.50 (2H, m), 3.25-2.87(6H, m), 2.19-2.03 (1H, m), 1.93-1.85 (1H, m), 1.84-1.65 (2H, m),0.95-0.86 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.04 (M−H) 445.

Example 8

(1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 1, starting frommethyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-ylmethyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 33), as a white solid.

¹H NMR (DMSO-d₆) δ: 7.92-7.86 (1H, m), 7.25 (1H, dd), 7.17 (1H, td),7.07 (1H, d), 6.97 (1H, d), 4.18 (1H, d), 3.62 (1H, d), 3.60-3.50 (1H,m), 3.40-3.06 (7H, m), 2.97-2.83 (1H, m), 2.17-2.04 (1H, m), 1.93-1.84(1H, m), 1.76-1.67 (1H, m), 1.66-1.53 (1H, m), 1.24 (6H, d), 0.96-0.87(1H, m), 0.74 (1H, q).

LCMS (Method C) r/t 3.17 (M−H) 517.

Example 9

(1aR,7bS)-5-[2-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 1, starting frommethyl(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 34), as a white solid.

¹H NMR (CDCl₃) δ: 8.21 (1H, br s), 8.12-8.05 (1H, m), 7.17-7.12 (1H, m),7.11-7.05 (1H, m), 7.03-6.96 (1H, m), 6.91-6.85 (1H, m), 4.45 (1H, d),3.91-3.81 (1H, m), 3.63-3.30 (3H, m), 3.30-3.02 (3H, m), 2.98-2.85 (1H,m), 2.57-2.44 (1H, m), 2.30-2.17 (1H, m), 2.00 (1H, s), 1.94-1.85 (2H,m), 1.85-1.76 (2H, m), 1.76-1.67 (1H, m), 1.06-0.94 (2H, m).

LCMS (Method C) r/t 3.18 (M−H) 485.

Examples 10 and 11

(1aR,7bS)-5-[2-((Z)-1-Azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid and(1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid.

Lithium hydroxide (0.08 g) was added to a solution of methyl(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(mixture of E and Z isomers, Intermediate 39, 0.095 g) in a mixture ofdioxane (3 mL) and water (1 mL) and the resultant mixture was irradiatedin the microwave at 150° C. with air cooling for 20 minutes. Aftercooling, the solution was acidified by addition of aqueous citric acidsolution (10%) and the mixture was extracted with DCM, dried (Na₂SO₄)and filtered. The filtrate was evaporated to dryness and the resultantresidue was purified by preparative HPLC (C18) eluting with a mixture ofacetonitrile and water, containing 0.1% formic acid, with a gradient of20-98% to give:

Example 10

(1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid as the first eluting isomer (0.017 g), as a white solid.

Structure confirmed by nOesy NMR experiments.

¹H NMR (DMSO-d₆) δ: 7.92 (1H, dd), 7.27-7.18 (2H, m), 6.99 (1H, d),6.91-6.86 (1H, m), 6.82 (1H, d), 4.17 (1H, d), 4.01 (2H, s), 3.61-3.14(5H, m), 2.74-2.68 (1H, m), 2.12-1.89 (4H, m), 2.12-1.81 (1H, m),1.74-1.65 (1H, m), 0.93-0.85 (1H, m), 0.76-0.69 (1H, m).

LCMS (Method C) r/t 3.19 (M−H) 483.

Example 11

(1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid as the second eluting isomer (0.011 g), as a white solid.

Structure confirmed by nOesy NMR experiments.

¹H NMR (DMSO-d₆) δ: 8.13 (1H, dd), 7.29 (1H, td), 7.01 (1H, dd), 6.92(1H, d,), 6.74 (1H, br m), 6.52 (1H, d), 4.21 (1H, d), 4.01 (2H, br s),3.53 (1H, d), 3.19-3.04 (4H, m), 2.65-2.61 (1H, m), 1.85-1.77 (1H, m),1.73-1.60 (3H, m), 1.52-1.34 (2H, m), 0.90-0.80 (1H, m), 0.70-0.64 (1H,m).

LCMS (Method C) r/t 3.27 (M−H) 483.

Examples 12 and 13

(1aR,7bS)-5-{2-[(E)-(1-Ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid and(1aR,7bS)-5-{2-[(Z)-(1-Ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

A mixture of methyl(1aR,7bS)-5-{2-[(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(mixture of E and Z isomers, Intermediate 41, 0.372 g) and lithiumhydroxide monohydrate (0.312 g) in water (2 mL) and dioxane (8 mL) washeated at 100° C. for 6 hours. After cooling, the volatiles were removedby evaporation and the residue was treated with citric acid (10%). Themixture was extracted with DCM and the organic layer was washed withbrine, dried (Na₂SO₄) and filtered. The filtrate was concentrated invacuo and the residue was purified by MDAP followed by HPLC (C18)eluting with a mixture of acetonitrile and water, containing 0.1% formicacid, with a gradient of 35-55% to give:

Example 12

(1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid as the first eluting isomer (0.06 g).

¹H NMR (DMSO-d₆) δ: 8.12 (1H, dd), 7.35-7.24 (2H, m), 7.05-7.01 (2H, m),6.93 (1H, d), 4.22 (1H, d), 3.85-3.73 (2H, m), 3.59 (2H, d), 3.17-3.08(3H, m), 2.46-2.36 (2H, m), 1.91-1.82 (1H, m), 1.76-1.61 (3H, m),1.43-1.34 (3H, m), 0.94-0.86 (1H, m), 0.76-0.69 (1H, m).

LCMS (Method C) r/t 3.42 (M−H) 485.

Example 13

(1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid as the second eluting isomer (0.016 g).

¹H NMR (DMSO-d₆) δ: 7.65-7.58 (1H, m), 7.22-7.15 (1H, m), 7.14-7.06 (3H,m), 6.98 (1H, d), 4.15 (1H, d), 3.69 (2H, br s), 3.56 (1H, d), 3.23-3.09(2H, br m), 2.98 (2H, br s), 2.47-2.38 (2H, m), 2.08-1.86 (3H, m),1.76-1.68 (1H, m), 1.13 (3H, t), 0.98-0.88 (1H, m), 0.74 (1H, q).

LCMS (Method C) r/t 3.51 (M−H) 485.

Examples 14 and 15

(1aR,7bS)-5-[2-((R)-1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid and(1aR,7bS)-5-[2-((S)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

A mixture of methyl(1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 45, 0.071 g) and lithium hydroxide monohydrate (0.059 g)in dioxane (5 mL) and water (2 mL) was stirred and heated at 100° C. for25 hours. Further lithium hydroxide monohydrate (0.116 g) was added andthe mixture was heated at 100° C. for a further 18 hours. After cooling,the volatiles were removed in vacuo and the residue was acidified byaddition of aqueous citric acid solution (10%) and saturated with sodiumchloride. The mixture was extracted with DCM and the organic layer wasdried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness andthe residue was purified by preparative HPLC (C18), eluting with amixture of acetonitrile and water, containing 0.1% formic acid, with agradient of 25-60%, to give a mixture of(1aR,7bS)-5-[2-((R)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid and(1aR,7bS)-5-[2-((S)-1-ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid (0.032 g) as a white solid.

This mixture was subjected to chiral separation using a ChiralPak ICcolumn, 10 mm×250 mm, particle size 5 micron. Eluting solvent: ethanol

Example 14

First eluting enantiomer: r/t on analytical column (4.6 mm×250 mm):18.21 minutes.

¹H NMR (DMSO-d₆) δ: 8.01-7.91 (1H, m), 7.26-7.18 (2H, m), 7.10-7.00 (2H,m), 4.20 (1H, d), 3.61 (1H, d), 3.24-2.89 (4H, m), 2.86-2.77 (1H, m),2.76-2.56 (2H, m), 1.94-1.85 (2H, m), 1.81-1.54 (4H, m), 1.30-1.14 (5H,m), 0.97-0.87 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.22 (M−H) 487.

Example 15

Second eluting enantiomer: r/t on analytical column (4.6 mm×250 mm):29.57 minutes.

¹H NMR (DMSO-d₆) δ: 8.01-7.91 (1H, m), 7.26-7.18 (2H, m), 7.10-7.00 (2H,m), 4.20 (1H, d), 3.61 (1H, d), 3.24-2.89 (4H, m), 2.79-2.58 (3H, m),1.95-1.86 (1H, m), 1.86-1.64 (4H, m), 1.62-1.45 (1H, m), 1.30-1.14 (5H,m), 0.97-0.87 (1H, m), 0.77-0.68 (1H, m).

LCMS (Method C) r/t 3.23 (M−H) 487.

Example 16

(1aR,7bS)-5-{2-[2-((S)-1-Ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Lithium hydroxide (0.11 g) was added to a solution of methyl(1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 53, 0.13 g) in a mixture of dioxane (6 mL) and water (2mL) and the resultant mixture was irradiated in the microwave at 150° C.with air cooling for 20 minutes. After cooling, the mixture wasacidified by addition of aqueous formic acid and extracted with DCM,dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness andthe residue was purified by MDAP to give(1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid (0.078 g) as a glass.

¹H NMR (DMSO-d₆) δ: 7.91-7.85 (1H, m), 7.32 (1H, dd), 7.15 (1H, td),7.06 (1H, d), 6.97 (1H, d), 4.17 (1H, d), 3.70-3.46 (4H, m), 3.18-2.94(4H, m), 2.28-2.15 (1H, m), 2.10-1.93 (4H, m), 1.91-1.80 (2H, m),1.75-1.64 (1H, m), 1.33-1.25 (3H, m), 0.96-0.86 (1H, m), 0.75-0.69 (1H,m).

LCMS (Method C) r/t 3.27 (M−H) 487.

Example 17

(1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 1, starting frommethyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 60), as white solid.

¹H NMR (DMSO-d₆) δ: 7.85 (1H, dd), 7.24 (1H, dd), 7.15 (1H, td), 7.06(1H, d), 6.97-6.90 (1H, m), 4.18 (1H, d), 3.68-3.56 (3H, m), 3.21-2.81(10H, m), 2.21-2.06 (1H, m), 1.92-1.84 (1H, m), 1.76-1.66 (1H, m),1.64-1.51 (1H, m), 0.96-0.86 (1H, m), 0.74 (1H, q).

LCMS (Method C) r/t 3.05 (M−H) 489.

Examples 18 and 19

(1aR,7bS)-5-[2-((Endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid and(1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 1, starting from amixture of exo and endo methyl(1aR,7bS)-5-[2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 62). The isomers were separated by preparative HPLC (C18).

Example 18

(1aR,7bS)-5-[2-((Endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

First Eluting Isomer

¹H NMR (DMSO-d₆) δ: 7.86 (1H, dd), 7.22-7.11 (2H, m), 7.05 (1H, d),6.99-6.92 (1H, m), 4.19 (1H, d), 3.89-3.80 (2H, br s), 3.61 (1H, d),3.18-3.03 (3H, m), 2.98-2.87 (2H, m), 2.35-2.12 (4H, m), 2.03-1.95 (2H,m), 1.92-1.83 (1H, m), 1.74-1.66 (1H, m), 1.49 (2H, dd), 1.21 (3H, t),0.94-0.86 (1H, m), 0.73 (1H, q).

LCMS (Method C) r/t 3.33 (M−H) 513.

Example 19

(1aR,7bS)-5-[2-((Exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Second Eluting Isomer

¹H NMR (DMSO-d₆) δ: 8.06 (1H, dd), 7.28 (1H, d), 7.19 (1H, td), 6.98(1H, d), 6.68 (1H, d), 4.22 (1H, d), 3.73-3.58 (3H, m), 2.95-2.75 (4H,m), 2.38-2.22 (1H, m), 2.01-1.91 (2H, m), 1.89-1.81 (1H, m), 1.76-1.40(7H, m), 1.26-1.16 (3H, m), 0.93-0.85 (1H, td), 0.77-0.71 (1H, m).

LCMS (Method C) r/t 3.35 (M−H) 513.

Example 20

(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

To a solution of methyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(Intermediate 67, 0.34 g) in 1,4-dioxane (20 mL) and water (10 mL) underan atmosphere of nitrogen was added lithium hydroxide monohydrate (0.248g). The resulting solution was heated at reflux for 18 hours. Aftercooling, the volatiles were removed by evaporation and the residue wasdiluted with water (30 mL) and the pH adjusted to 4 by addition of anaqueous solution of formic acid. The mixture was extracted with ethylacetate and THF (1:1 mixture) and the combined organic layers were dried(Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and theresidue was purified by HPLC to give(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid (0.106 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 7.65 (1H, d), 7.58-7.48 (1H, m), 7.26 (1H, m),7.16-7.10 (1H, m), 6.87 (1H, ddd), 6.71 (1H, dt), 5.99-5.89 (1H, m),4.28 (1H, d), 4.14-3.94 (1H, m), 3.81-3.58 (3H, m), 3.49-3.22 (2H, m),3.04 (1H, dd), 2.20-2.07 (1H, m), 2.06 (1H, m), 1.92-1.82 (1H, m),1.68-1.59 (1H, m), 1.26 (3H, s), 1.09-1.01 (1H, m), 0.96-0.87 (1H, m).

LCMS (Method C) r/t 3.06 (M+H) 503

Example 21

(1aR,7bS)-5{4-Fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 20, starting frommethyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 71), as an off-white solid.

¹H NMR (DMSO-d₆) δ: 7.63 (1H, d), 7.45-7.37 (1H, m), 7.18-7.10 (2H, m),6.84 (1H, dt), 6.73 (1H, dd), 6.06-5.96 (1H, m), 4.27 (1H, d), 4.08-3.99(1H, m), 3.98-3.90 (1H, m), 3.69 (1H, d), 3.50-3.40 (1H, m), 3.35-3.11(4H, m), 2.16-2.03 (2H, m), 1.93-1.84 (2H, m), 1.85-1.74 (1H, m),1.69-1.59 (1H, m), 1.08-1.00 (1H, m), 0.97-0.88 (1H, m).

LCMS (Method C) r/t 3.06 (M+H) 503.

Example 22

(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 20, starting frommethyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 72), as a light yellow solid.

¹H NMR (DMSO-d₆) δ: 7.58 (1H, m), 7.28 (1H, d), 7.18 (1H, dt), 7.13 (1H,dd), 7.07 (1H, d), 6.90 (1H, d), 6.22-6.12 (1H, m), 4.63 (1H, m), 4.12(1H, d), 3.78-3.57 (1H, m), 3.54 (1H, d), 3.11-2.84 (5H, m), 1.93-1.84(1H, m), 1.73-1.64 (1H, m), 1.64-1.50 (3H, m), 1.12 (3H, s), 0.94-0.84(1H, m), 0.73-0.65 (1H, m).

LCMS (Method C) r/t 3.16 (M+H) 517.

Example 23

(1aR,7bS)-5-[2-(3-Ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

A suspension of methyl(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 73, 0.247 g) and lithium hydroxide monohydrate (0.214 g)in dioxane (6 mL) and water (3 mL) was heated at 80° C. for 18 hoursunder an atmosphere of nitrogen. After cooling, the volatiles wereremoved in vacuo and the residue was acidified by addition of aqueouscitric acid solution (10%). The mixture was extracted with DCM and theorganic layer was dried (Na₂SO₄) and filtered. The filtrate wasevaporated to dryness and the residue was purified by MDAP to give(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid (0.13 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 8.08 (1H, dd), 7.28-7.15 (2H, m), 7.06 (1H, d), 6.89(1H, d), 4.20 (1H, d), 3.90-3.80 (2H, m), 3.65 (1H, d), 3.40-3.30 (2H,m), 3.28-3.18 (2H, m), 2.51-2.45 (1H, m), 2.38-2.27 (2H, m), 1.93-1.85(1H, m), 1.77-1.68 (1H, m), 1.34 (3H, t), 0.97-0.88 (1H, m), 0.78-0.72(1H, m).

LCMS (Method C) r/t 3.17 (M−H) 471.

Example 24

(1aR,7bS)-5-{4-Fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 1, starting frommethyl(1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(Intermediate 78), as an off-white powder (0.028 g).

¹H NMR (DMSO-d₆) δ: 7.49 (1H, dd), 7.21-7.06 (4H, m), 6.98 (1H, dd),5.96-5.89 (1H, m), 4.12 (1H, d), 3.94-3.80 (1H, m), 3.47 (1H, d), 3.16(2H, t), 2.35-2.23 (1H, m), 2.03-1.85 (3H, m), 1.77-1.65 (2H, m),0.95-0.86 (1H, m), 0.73-0.64 (1H, m).

LCMS (Method C) r/t 3.31 (M−H) 457.

Example 25

(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 20, starting frommethyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 82), as an off-white solid.

¹H NMR (CDCl₃) δ: 7.64 (1H, d), 7.52 (1H, dd), 7.21 (1H, d), 7.12 (1H,d), 6.86 (1H, dt), 6.71 (1H, dd), 5.98-5.89 (1H, m), 4.26 (1H, d),3.98-3.83 (1H, m), 3.71 (1H, d), 3.64-3.48 (5H, m), 3.32-3.19 (1H, m),3.18-3.06 (1H, m), 2.66-2.54 (1H, m), 2.20-2.08 (1H, m), 1.91-1.74 (2H,m), 1.67-1.59 (1H, m), 1.06-0.98 (1H, m), 0.95-0.88 (1H, m).

LCMS (Method C) r/t 3.13 (M+H) 503.

Example 26

(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 20, starting frommethyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 85), as a white solid.

¹H NMR (CDCl₃) δ: 7.65 (1H, d), 7.50 (1H, d), 7.21 (1H, d), 7.14 (1H,d), 6.85 (1H, dt), 6.71 (1H, dd), 5.98-5.88 (1H, m), 4.27 (1H, d), 4.19(1H, m), 3.84-3.70 (1H, m), 3.69 (1H, d), 3.63-6.43 (4H, m), 3.24-3.12(1H, m), 3.12-3.00 (1H, m), 2.66-2.53 (1H, m), 2.24-2.11 (1H, m),1.92-1.84 (1H, m), 1.84-1.73 (1H, m), 1.68-1.59 (1H, m), 1.09-1.02 (1H,m), 0.96-0.88 (1H, m).

LCMS (Method C) r/t 3.13 (M+H) 503.

Example 27

(1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 20, starting frommethyl(1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzene-sulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 86), as a white solid.

¹H NMR (CDCl₃) δ: 7.63 (1H, d), 7.48-7.40 (1H, m), 7.19 (1H, d), 7.11(1H, d), 6.83 (1H, dt), 6.70 (1H, dd), 5.97-5.88 (1H, m), 4.26 (1H, d),4.02-3.84 (1H, m), 3.70 (1H, d), 3.69-3.11 (5H, m), 2.44-2.32 (1H, m),2.08-1.98 (2H, m), 1.91-1.83 (1H, m), 1.67-1.59 (1H, m), 1.21 (3H, s),1.19 (3H, s), 1.07-0.98 (1H, m), 0.95-0.87 (1H, m).

LCMS (Method C) r/t 3.31 (M+H) 531.

Example 28

(1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 20, starting frommethyl(1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzene-sulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 87), as a white solid.

¹H NMR (CDCl₃) δ: 7.63 (1H, d), 7.47-7.39 (1H, m), 7.19 (1H, d), 7.12(1H, d), 6.83 (1H, dt), 6.70 (1H, dd), 5.98-5.88 (1H, m), 4.27 (1H, d),4.19 (1H, m), 3.67 (1H, d), 3.58-3.13 (5H, m), 2.43-2.31 (1H, m),2.10-1.99 (2H, m), 1.92-1.83 (1H, m), 1.67-1.58 (1H, m), 1.22 (3H, s),1.18 (3H, s), 1.10-1.02 (1H, m), 0.96-0.87 (1H, m).

LCMS (Method C) r/t 3.31 (M+H) 531.

Example 29

(1aR,7bS)-5-[4-Fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

A mixture of methyl(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 88, 0.09 g) and lithium hydroxide monohydrate (0.076 g) indioxane (7 mL) and water (3 mL) was heated at 80° C. under an atmosphereof nitrogen for 20 hours. Further lithium hydroxide monohydrate (0.152g) and water (4 mL) were added and the temperature raised to 100° C.After 6.5 hours stirring at that temperature, the reaction mixture wascooled to room temperature and the volatiles were removed in vacuo. Theresidue was acidified by addition of aqueous citric acid solution (10%)and the mixture was extracted with DCM. The organic layer was dried(Na₂SO₄), filtered and the filtrate was evaporated to dryness. Theresidue was purified by preparative HPLC (C18) eluting with a mixture ofacetonitrile and water, containing 0.1% formic acid, with a gradient of25-40% to give(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid (0.031 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 7.98-7.90 (1H, m), 7.22-7.15 (2H, m), 7.03 (1H, dd),6.94 (1H, t), 4.20-4.04 (2H, m), 3.60 (1H, t), 3.45-2.97 (4H, m),2.76-2.63 (1H, m), 2.62-2.50 (1H, m), 2.25-1.82 (6H, m), 1.76-1.63 (2H,m), 1.47-1.35 (1H, m), 0.94-0.85 (1H, m), 0.75-0.67 (1H, m).

LCMS (Method C) r/t 3.16 (M+H) 487.

Example 30

(1aR,7bS)-5-{2-[((S)-1-Ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 1, starting frommethyl(1aR,7bS)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 96), as a white solid.

¹H NMR (DMSO-d₆) δ: 9.55 (1H, s), 7.59 (1H, dd), 7.34 (1H, dd),7.20-7.10 (2H, m), 7.04 (1H, d), 4.49-4.41 (1H, m), 4.13 (1H, d), 3.86(1H, d), 3.72 (1H, d), 3.62 (1H, d), 3.59-3.47 (1H, m), 3.31 (1H, d),3.20-3.07 (2H, m), 3.06-2.95 (2H, m), 2.46-2.31 (1H, m), 1.99-1.90 (2H,m), 1.78-1.68 (1H, m), 1.20 (3H, t), 0.99-0.92 (1H, m), 0.81-0.74 (1H,m).

LCMS (Method C) r/t 3.01 (M−H) 516.

Example 31

(1aR,7bS)-5-[2-((3R)-1-Ethylpyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid

Prepared by proceeding in a similar manner to Example 16, starting frommethyl(1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(Intermediate 102) as a white solid

¹H NMR (DMSO-d₆) δ: 7.77 (1H, dd), 7.53 (1H, td), 7.38 (1H, d), 7.31(1H, t), 7.11-6.99 (2H, m), 4.16 (1H, d), 3.64-3.52 (2H, m), 3.24-2.92(8H, m), 2.29-2.16 (1H, m), 1.93-1.85 (1H, m), 1.74-1.62 (2H, m), 1.22(3H, t), 0.95-0.88 (1H, m), 0.73 (1H, q).

LCMS (Method C) r/t 3.11 (M−H) 455.

Example 32

(1aR,7bS)-5-{2-R(S)-1-ethylpyrrolidine-3-carbonyl)aminomethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid-formic acid (1:1)

Methyl(1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)aminomethyl]-4-fluoro-benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 106, 0.207 g) and lithium hydroxide monohydrate (0.164 g)were suspended in dioxane (12 mL) and water (6 mL) and the mixture washeated at 100° C. for 5.5 hours under an atmosphere of nitrogen. Aftercooling, the mixture was acidified to pH3 by addition of aqueous citricacid solution (10%) and extracted with DCM. The organic layer was dried(Na₂SO₄) and filtered and the filtrate was evaporated to dryness. Theresidue was purified by preparative HPLC (C18) eluting with a mixture ofacetonitrile and water, containing 0.1% formic acid, with a gradient of25-60%. The resultant solid was dissolved in dioxane (5 mL) and water (5mL), treated with lithium hydroxide monohydrate (0.164 g) and heated at80° C. for 2 days. After cooling, the mixture was acidified to pH3 byaddition of aqueous citric acid solution (10%) and extracted with DCM.The organic layer was dried (Na₂SO₄) and filtered and the filtrate wasevaporated to dryness. The residue was purified by preparative HPLC(C18) eluting with a mixture of acetonitrile and water, containing 0.1%formic acid, with a gradient of 25-60% to give(1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid-formic acid (1:1) (0.052 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 8.78 (1H, q), 8.14 (1H, s), 7.89-7.82 (1H, m), 7.19(1H, td), 7.12 (1H, dt), 7.02 (1H, dd), 6.75 (1H, dd), 4.74 (2H, d),4.19 (1H, d), 3.62 (1H, d), 3.50-3.15 (5H, m), 3.10 (2H, q), 2.35-2.23(1H, m), 2.10-1.99 (1H, m), 1.91-1.81 (1H, m), 1.75-1.67 (1H, m), 1.20(3H, t), 0.93-0.86 (1H, m), 0.75-0.70 (1H, m).

LCMS (Method C) r/t 3.01 (M−H) 516.

Example 33

(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro-benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid-formic acid (1:1)

A mixture of methyl(1aR,7bS)-5-(2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 115, 0.048 g) and lithium hydroxide (0.033 g) in dioxane(1 mL) and water (0.4 mL) was irradiated in the microwave at 150° C. for30 minutes. After cooling, the volatiles were removed by evaporation andthe residue was partitioned between 10% aqueous citric acid and DCM. Thecombined aqueous and organic layers were loaded onto an SCX column andthe column was washed with methanol. The product was eluted off thecolumn with 2M ammonia in methanol. The resultant material was purifiedby preparative HPLC (C18) eluting with a mixture of acetonitrile andwater, containing 0.1% formic, with a gradient of 20-98% to give(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid-formic acid (1:1) (0.019 g) as a white solid.

¹H NMR (DMSO-d₆) δ: 8.13 (1H, s), 7.81 (1H, dd), 7.22 (1H, dd), 7.10(1H, dt), 7.00 (1H, d), 6.88 (1H, d), 4.13 (1H, d), 3.57 (1H, d),3.52-3.45 (1H, m), 3.18-3.03 (4H, m), 2.96-2.69 (6H, m), 2.16-2.05 (1H,m), 1.87-1.79 (1H, m), 1.79-1.70 (1H, m), 1.69-1.61 (1H, m), 1.11 (3H,t), 0.90-0.82 (1H, m), 0.72-0.66 (1H, m).

LCMS (Method C) r/t 2.62 (M+H) 504.

Intermediate 1 Methyl(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

A mixture of methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethylcyclopropyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 2, 0.227 g) and diethylamine (1 mL) in DCE (2.5 mL) washeated at 45° C. in a sealed vial for 6 hours. The volatiles wereremoved by evaporation and the residue was purified by chromatography onsilica, eluting with a mixture of methanol and ethyl acetate, with agradient of 0-20% to givemethyl(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(0.063 g) as a white solid.

LCMS (Method A) r/t 2.49 (M+H) 503.

Intermediate 2 Methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethyl-cyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A solution of methanesulfonyl chloride (0.12 g) in DCM (2 mL) was addedto a mixture of methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-hydroxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 3, 0.43 g), DMAP (0.01 g) and triethylamine (0.24 mL) inDCM (15 mL). The mixture was stirred at room temperature for 30 minutesand then the volatiles were removed by evaporation. The residue waspurified by chromatography on silica, eluting with a mixture of ethylacetate and cyclohexane, with a gradient of 0-80%, to give methyl1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.49 g) as a white solid.

LCMS (Method A) r/t 3.49 (M+Na) 606.

Intermediate 3 Methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-hydroxymethylcyclopropyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Concentrated hydrochloric acid (20 mL) was added to a solution of methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-methoxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 4, 0.97 g) in methanol (5 mL) and dioxane (10 mL). Themixture was stirred at 20° C. for 5 hours then the volatiles wereremoved by evaporation. The residue was partitioned between ethylacetate and water. The aqueous phase was further extracted with ethylacetate and the combined organic layers were dried (Na₂SO₄) andfiltered. The filtrate was evaporated to dryness and the residue waspurified by chromatography on silica, eluting with a mixture of ethylacetate and cyclohexane with a gradient of 0-100%, to give methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-hydroxymethylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(1.01 g) as a colourless oil.

LCMS (Method A) r/t 3.20 (M+Na) 528.

Intermediate 4 Methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-methoxymethoxymethyl-cyclopropyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A mixture of methyl chloroformate (1.03 g) in DCM (20 mL) was slowlyadded to a solution of methyl(1aR,7bS)-5-[4-fluoro-2-(2-methoxymethoxymethylcyclopropyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 5, 1.07 g) and pyridine (15 mL) in DCM (10 mL) at 0° C.under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 15minutes and then at 20° C. Further methyl chloroformate (0.5 g and 0.28g) were added after 3 hours and 4 hours stirring, respectively. Stirringat room temperature was continued for 1 hour then the volatiles wereremoved by evaporation. The residue was partitioned between DCM andwater and the organic layer was dried (Na₂SO₄) and filtered. Thefiltrate was concentrated in vacuo and the residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane with a gradient of 0-60%, to give methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-methoxymethoxy-methylcyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(1.2 g) as a colourless oil.

LCMS (Method A) r/t 3.69 (M+Na) 572.

Intermediate 5 Methyl(1ar,7bs)-5-[4-fluoro-2-(2-methoxymethoxymethylcyclopropyl)-benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl(1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 6, 0.6 g),2-[2-(methoxymethoxymethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Intermediate 7, 0.38 g), tris-(dibenzylideneacetone)dipalladium (0.12g), tri-tert-butylphosphonium tetrafluoroborate (0.05 g) and cesiumcarbonate (1.71 g) in dioxane (10 mL) and water (3 mL) was degassed witha stream of argon and irradiated in the microwave at 150° C. for 45minutes. The reaction was repeated a further two times using the sameamount of reagents under the reaction conditions described above. Thecombined reaction mixtures were partitioned between ethyl acetate andwater. The aqueous phase was further extracted with ethyl acetate andthe combined organic layers were dried (Na₂SO₄) and filtered. Thefiltrate was concentrated in vacuo and the residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 0-50%, to give methyl(1aR,7bS)-5-[4-fluoro-2-(2-methoxymethoxymethylcyclopropyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(1.12 g) as a gum.

LCMS (Method A) r/t 3.79 (M+Na) 514.

Intermediate 6 Methyl(1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

2-Bromo-4-fluorobenzenesufonyl chloride (4.48 g) was added portionwiseto a stirred solution of methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 2.99 g) and pyridine (15 mL) in DCM (25 mL) at 0° C.The mixture was stirred at 0° C. under an atmosphere of nitrogen for 10minutes and then at room temperature for 2 hours. The volatiles wereremoved by evaporation and the residue was partitioned between DCM and1M aqueous hydrochloric acid solution. The aqueous phase was extractedwith DCM and the organic layer was dried (Na₂SO₄) and filtered. Thefiltrate was concentrated in vacuo and the residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 0-50%, to give methyl(1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(6.02 g) as a white solid.

¹H NMR (CDCl₃) δ: 9.31 (1H, br, s), 8.14 (1H, dd), 7.41 (1H, dd), 7.17(1H, d), 7.11 (1H, ddd), 7.06 (1H, d), 4.34 (1H, dd), 3.90 (3H, s), 3.80(1H, dd), 1.94-1.85 (1H, m), 1.75-1.67 (1H, m), 1.01 (2H, m).

Intermediate 72-[2-(Methoxymethoxymethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Diiodomethane (5.5 mL) was added to a mixture of diethylzinc (1.1M intoluene, 52 mL) in DCM (16 mL) at 0° C. under an atmosphere of nitrogen.The mixture was stirred at 0° C. for 10 minutes then a solution of2-((Z)-3-methoxymethoxyprop-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(5.18 g) in DCM (20 mL) was added over 10 minutes. The mixture wasstirred at 0° C. for 15 minutes, then at 20° C. for 16 hours. Theresultant mixture was cooled to 0° C. and added by a cannula to asolution of diiodomethane (3.3 mL) and diethylzinc (1.1M in toluene, 31mL) in DCM (10 mL) at 0° C. The mixture was stirred at 0° C. for 15minutes, then at 20° C. for 16 hours. The mixture was poured into asaturated solution of ammonium chloride and extracted with ethylacetate, dried (Na₂SO₄) and filtered. The filtrate was concentrated invacuo and the residue was purified by chromatography on silica, elutingwith a mixture of ethyl acetate and cyclohexane, with a gradient of0-30%, to give2-[2-(methoxymethoxymethyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a colourless oil (3.03 g).

¹H NMR (CDCl₃) δ: 4.67-4.60 (2H, m), 3.68 (1H, dd), 3.48 (1H, dd), 3.38(3H, s), 1.47-1.36 (1H, m), 1.22 (12H, d), 0.92-0.85 (1H, m), 0.56-0.50(1H, m), 0.09-0.01 (1H, m).

Intermediate 8 Methyl(1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methyl5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 9, 0.310 g) was suspended in methanol (7.5 mL) andconcentrated sulfuric acid (4 drops) was added. The mixture was heatedat reflux, under an atmosphere of nitrogen, for 36 hours. A further 2drops of concentrated sulfuric acid was added and heating was continuedfor a further 24 hours. After cooling, the mixture was concentrated invacuo and the residue was partitioned between ethyl acetate andsaturated aqueous potassium carbonate solution. The aqueous layer wasextracted with ethyl acetate and the combined organic layers were dried(Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and theresidue was purified by chromatography on silica, eluting with a mixtureof ethyl acetate and cyclohexane, with a gradient of 5-20%, to givemethyl 5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.120 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 7.06 (1H, d), 6.26 (1H, d), 4.33 (1H, d), 3.87 (3H,s), 3.85 (1H, d), 1.83 (1H, td), 1.64 (1H, m), 0.99-0.89 (2H, m).

Intermediate 8A Methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Sample from Intermediate 8 was subjected to chiral SFC separation usinga Lux C-3 column, 50 mm×250 mm, particle size 5 micron. Eluting with 5%methanol (+0.1% diethylamine) in CO₂ to give methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylateas the first eluting enantiomer.

Intermediate 9 Methyl5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Methyl1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 10, 1.13 g) was suspended in ethanol (30 mL). Zinc dust(1.17 g), followed by ammonium chloride (1.31 g) were added and themixture was heated at reflux, under an atmosphere of nitrogen, for 6hours. After cooling, the solid was filtered off and washed with ethylacetate. The filtrate was concentrated in vacuo and the residue waspurified by chromatography on silica, eluting with a mixture of etherand cyclohexane, with a gradient of 5-12.5%, to give methyl5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.310 g) as a colourless oil.

¹H NMR (CDCl₃) δ: 9.72 (1H, br, s), 7.98 (1H, d), 7.30 (1H, d), 4.36(1H, dd), 3.91 (3H, s), 3.84 (1H, dd), 1.95 (1H, td), 1.73 (1H, m), 1.28(9H, s), 1.03 (2H, m).

Intermediate 10 Methyl1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate(Intermediate 11, 2.372 g) and benzyl triethyl ammonium chloride (0.373g) were suspended in bromoform (6.45 mL) and 50% aqueous sodiumhydroxide solution (3.64 mL) was added dropwise. The resultant blacksuspension was heated at 60° C. for 2 hours. After cooling, the mixturewas partitioned between water and ethyl acetate. The emulsion formed wasfiltered through a pad of Celite and the organic layer was decanted off.The aqueous was re-extracted with ethyl acetate and the combined organiclayers were dried (MgSO₄) and filtered. The filtrate was concentrated invacuo and the residue was purified by chromatography on silica, elutingwith a mixture of ethyl acetate and cyclohexane, with a gradient of2.5-15%, to give methyl1,1-dibromo-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(1.557 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 9.89 (1H, br, s), 8.13 (1H, d), 7.43 (1H, d), 4.47(1H, dd), 4.32 (1H, dd), 3.91 (3H, s), 2.89 (1H, d), 2.45 (1H, ddd),1.30 (9H, s).

Intermediate 11 Methyl7-(2,2-dimethylpropionoylamino)-2H-chromene-8-carboxylate

A solution of methyl2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (Intermediate12, 4.74 g) and[bis(trifluoromethanesulfonyl)imidate]-(triphenylphosphine)-gold (2:1)toluene adduct (0.06 g) in toluene (70 mL) was heated at 85° C., underan atmosphere of nitrogen for 3 hours. After cooling, the mixture wasconcentrated in vacuo and the residue was purified by chromatography onsilica, eluting with a mixture of ethyl acetate and cyclohexane, with agradient of 0-20%, to give methyl7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (3.59 g) as acolourless oil.

¹H NMR (CDCl₃) δ: 10.02 (1H, br, s), 8.05 (1H, d), 7.05 (1H, d), 6.39(1H, ddd), 5.76 (1H, dt), 4.83 (2H, dd), 3.93 (3H, s), 1.30 (9H, s).

Intermediate 12 Methyl2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate

A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate(Intermediate 13, 4.57 g), propargyl bromide (80% solution in toluene,2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heatedat reflux for 8 hours. After cooling, the mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 5-20%, to give methyl2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as anoil which crystallised on standing to give a white solid.

¹H NMR (CDCl₃) δ: 9.89 (1H, br, s), 8.16 (1H, dd), 7.41 (1H, t), 6.83(1H, dd), 4.74 (2H, d), 3.95 (3H, s), 2.53 (1H, t), 1.31 (9H, s).

Intermediate 13 Methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate

Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl2-amino-6-hydoxybenzoate (prepared according to Comess et al, US20040167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77mL) and water (18 mL). The mixture was stirred at room temperature for 1hour. A further amount of trimethylacetyl chloride (1.85 g) was addedand the mixture was stirred for 1 hour. A further amount oftrimethylacetyl chloride (0.920 g) was added and the mixture was stirredfor 30 minutes. The mixture was diluted with ethyl acetate, the layerswere separated and the organic layer was dried (Na₂SO₄) and filtered.The filtrate was concentrated in vacuo and the residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 5-25%, to give methyl2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a whitesolid.

¹H NMR (CDCl₃) δ: 10.32 (1H, br, s), 8.22 (1H, dd), 7.41 (1H, t), 6.71(1H, dd), 4.08 (3H, s), 1.33 (9H, s).

Intermediate 14 Methyl(1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)-cyclopropyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl(1aR,7bS)-5-{N-[4-fluoro-2-(2-methanesulfonyloxymethyl-cyclopropyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 2, 0.15 mg) and pyrrolidine (0.7 mL) in DCE (2 mL) washeated at 45° C. in a sealed vial for 3 hours. The volatiles wereremoved by evaporation and the residue was purified by chromatography onsilica, eluting with a mixture of methanol and ethyl acetate, with agradient of 0-20%, to give methyl(1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(0.077 g).

LCMS (Method A) r/t 2.37 (M+H) 501.

Intermediate 15 Methyl(1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Sodium triacetoxyborohydride (0.335 g) was added to a solution of methyl(1aR,7bS)-5-[2-(2,2-dimethyl-3-oxopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 16, 0.366 g) and diethylamine (0.173 g) in DCM (5 mL) andthe mixture was stirred at room temperature for 3 days then left tostand for 4 days. The mixture was diluted with DCM and washed withwater, dried (Na₂SO₄) and filtered. The filtrate was concentrated invacuo and the residue was purified by chromatography on silica, elutingwith a mixture of methanol and DCM, with a gradient of 0-12%, to givemethyl(1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.138 g) as a colourless gum.

LCMS (Method D) r/t 2.66 and 2.79 (M+H) 519.

Intermediate 16 Methyl(1aR,7bS)-5-[2-(2,2-dimethyl-3-oxopropyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of methyl(1aR,7bS)-5-{2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 17, 0.41 g) in water (2 mL), THF (20 mL) and concentratedhydrochloric acid (2 mL) was heated at 60° C. for 90 minutes. Aftercooling, the volatiles were removed by evaporation and the residue waspartitioned between water and DCM. The organic layer was dried (Na₂SO₄)and filtered and the filtrate was concentrated in vacuo to give methyl(1aR,7bS)-5-[2-(2,2-dimethyl-3-oxopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.371 g) as a colourless gum.

LCMS (Method D) r/t 4.14 (M+Na) 484.

Intermediate 17 Methyl(1aR,7bS)-5-{2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A solution of2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylchloride (Intermediate 18, 0.484 g) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 8A, 0.219 g) in pyridine (2 mL) and DCM (4 mL) was left tostand at room temperature for 17 hours. The volatiles were removed byevaporation and the residue was partitioned between DCM and water. Theorganic layer was dried (Na₂SO₄) and filtered and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography onsilica, eluting with a mixture of ethyl acetate and cyclohexane, with agradient of 0-30%, to give methyl(1aR,7bS)-5-{2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylateas a colourless gum (0.415 g).

LCMS (Method D) r/t 4.36 (M+Na) 528.

Intermediate 182-[2-(1,3-Dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzenesulfonylchloride

n-Butyllithium (1.6M in hexanes, 4.7 mL) was added to a solution of2-[1-(2-bromo-5-fluorophenyl)-2-methylpropan-2-yl]-1,3-dioxolane(Intermediate 19, 2.13 g) in anhydrous THF (40 mL) at −78° C. under anatmosphere of nitrogen. The mixture was stirred for 30 minutes thensulfur dioxide was bubbled through the solution for 30 minutes. Thecooling bath was removed and the mixture was allowed to warm to roomtemperature slowly. The volatiles were removed by evaporation and amixture of N-chlorosuccinimide (0.94 g) in DCM (40 mL) was added to theresidue. The mixture was stirred at room temperature for 30 minutes andthen washed with water, dried (Na₂SO₄) and filtered and the filtrate wasconcentrated in vacuo to give2-[2-(1,3-dioxolan-2-yl)-2-methylpropyl]-4-fluorobenzene-sulfonylchloride (1.86 g) as a pale coloured oil.

¹H NMR (CDCl₃) δ: 8.15 (1H, dd), 7.14-7.06 (1H, m), 6.95-6.84 (1H, m),4.68 (1H, s), 4.02-3.84 (4H, m), 3.26 (2H, s), 0.96 (6H, s).

Intermediate 192-[1-(2-Bromo-5-fluorophenyl)-2-methylpropan-2-yl]-1,3-dioxolane

A mixture of 3-(2-bromo-5-fluorophenyl)-2,2-dimethylpropanal(Intermediate 20, 2.59 g), 4-toluenesulfonic acid (0.19 g) and ethyleneglycol (3.1 g) in toluene (50 mL) was stirred and heated at reflux witha Dean-Stark apparatus for 3 hours. After cooling, the mixture waswashed with a saturated solution of sodium bicarbonate and water, dried(Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and theresidue was purified by chromatography on silica, eluting with a mixtureof ethyl acetate and cyclohexane, with a gradient of 0-5%, to give2-[1-(2-bromo-5-fluorophenyl)-2-methylpropan-2-yl]-1,3-dioxolane (2.65g) as a pale coloured oil.

¹H NMR (CDCl₃) δ: 7.50 (1H, dd), 7.02 (1H, dd), 6.84-6.76 (1H, m), 4.64(1H, s), 4.04-3.88 (4H, m), 2.88 (2H, s), 0.95 (6H, s).

Intermediate 20 3-(2-Bromo-5-fluorophenyl)-2,2-dimethylpropanal

A solution of 2-methylpropionaldehyde (1.19 g) and2-bromomethyl-4-fluorobromobenzene (4.02 g) in toluene (2 mL) was addedto a stirred suspension of ground NaOH (0.66 g) and tetrabutyl ammoniumiodide (0.111 g) in toluene (9 mL) at 60° C. under an atmosphere ofnitrogen. The mixture was stirred at 60° C. for 20 hours and then leftto stand at room temperature for 3 days. The mixture was partitionedbetween ethyl acetate and water and the organic layer was dried (Na₂SO₄)and filtered. The filtrate was concentrated in vacuo and the residue waspurified by chromatography on silica, eluting with a mixture of ethylacetate and cyclohexane, with a gradient of 0-5%, to give3-(2-bromo-5-fluorophenyl)-2,2-dimethylpropanal (2.61 g) as a colourlessoil.

¹H NMR (CDCl₃) δ: 9.60 (1H, s), 7.49 (1H, dd), 6.95-6.76 (2H, m), 3.01(2H, s), 1.12 (6H, s).

Intermediate 21 Methyl(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

A mixture of methyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 22, 2.13 g) and potassium carbonate (2.76 g) in methanol(30 mL) was stirred at room temperature for 1.5 hour, then heated at 55°C. for 1 hour. After cooling, the volatiles were removed by evaporationand the residue was partitioned between water and ethyl acetate. Theaqueous phase was acidified by addition of acetic acid and extractedwith ethyl acetate, dried (Na₂SO₄) and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by chromatography onsilica, eluting with a mixture of methanol and DCM, with a gradient of0-40%, to give methyl(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(1.14 g) as a light coloured foam.

LCMS (Method D) r/t 4.48 and 4.62 (M+H) 461.

Intermediate 22 Methyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylchloride (Intermediate 23, 1.7 g) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.996 g) in pyridine (5 mL) and DCM (5 mL) was left tostand at room temperature for 4 hours. The volatiles were removed byevaporation and the residue was partitioned between DCM and 2M aqueoushydrochloric acid. The organic layer was dried through a phase separatorand then concentrated in vacuo. The residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 0-35%, to give methyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(2.17 g) as a white foam.

LCMS (Method D) r/t 4.15 and 4.21 (M+Na) 579.

Intermediate 234-Fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylchloride

Chlorosulphonic acid (6 mL) was added to an ice-cooled solution of2,2,2-trifluoro-1-[(R)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone(Intermediate 24, 2.0 g) in chloroform (10 mL). The cooling bath wasremoved and the mixture was stirred at room temperature 45 minutes. Themixture was poured into a mixture of ice and ethyl acetate and theorganic phase was washed with a saturated solution of sodiumbicarbonate, then dried (Na₂SO₄) and filtered. The filtrate wasconcentrated in vacuo to give4-fluoro-2-[(R)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylchloride (1.72 g) as a colourless and viscous gum.

LCMS (Method D) r/t 4.16 (M+H) 374.

Intermediate 242,2,2-Trifluoro-1-[(R)-3-(3-fluorobenzyl)pyrrolidin-1yl]ethanone

A solution of tert-butyl (R)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate(Intermediate 25 (2.21 g) in TFA (10 mL) and DCM (10 mL) was left tostand at room temperature for 30 minutes. The mixture was concentratedin vacuo and the residue was azeotroped with toluene. The residue wasdissolved in DCM (30 mL) and cooled in an ice bath. A mixture oftriethylamine (2.52 g) and trifluoroacetic anhydride (2.1 g) was addedand the mixture was then stirred for 30 minutes. The mixture was washedwith water and filtered through a phase separator. The filtrate wasconcentrated in vacuo and the residue was purified by chromatography onsilica, eluting with a mixture of ethyl acetate and cyclohexane, with agradient of 0-20%, to give2,2,2-trifluoro-1-[(R)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone (2.02g) as a colourless oil.

LCMS (Method D) r/t 4.04 (M+H) 276.

Intermediate 25 tert-Butyl(R)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate

Nickel Iodide (0.147 g), trans-2-aminocyclohexanol HCl salt (0.74 g),3-fluorobenzene boronic acid (0.78 g) and sodium hexamethyldisilazide(0.208 g) were placed in a sealed tube and the mixture was degassed andpurged with argon. Isopropanol (8 mL) was added and the mixture wasstirred and heated at 40° C. for 5 minutes. A solution of tert-butyl(R)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate 26, 1.44 g) inisopropanol (8 mL) was added and the mixture was heated at 70° C.overnight. After cooling, the mixture was diluted with ethyl acetate,filtered through Celite and the filtrate was evaporated to dryness. Theresidue was purified by chromatography on silica, eluting with a mixtureof ethyl acetate and cyclohexane, with a gradient of 0-60%, to givetert-butyl (3R)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate (0.515 g) asan oil.

¹H NMR (CDCl₃) δ: 7.27-7.21 (2H, m), 6.95-6.84 (2H, m), 3.51-3.39 (2H,m), 3.31-3.19 (1H, m), 2.98 (1H, dd), 2.69-2.62 (2H, m), 2.47-2.30 (1H,m), 1.98-1.85 (1H, m), 1.64-1.47 (1H, m), 1.46 (9H, s).

Intermediate 26 tert-Butyl (R)-3-iodomethylpyrrolidine-1-carboxylate

Iodine (1.91 g) was added in portions to a vigorously stirred, icecooled suspension of imidazole (0.681 g) and triphenylphosphine (1.97 g)in diethyl ether (12 mL). The reaction mixture was stirred for 10minutes before a solution of tert butyl(R)-3-hydroxymethylpyrrolidine-1-carboxylate (1 g) in dioxane (6 mL) wasadded dropwise. The mixture was stirred at room temperature overnight,then diluted with diethyl ether and filtered. The solid was washed withdiethyl ether and the combined filtrates were evaporated to dryness. Theresidue was purified by chromatography on silica, eluting with a mixtureof ethyl acetate and pentane, with a gradient of 0-20%, to givetert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (1.44 g) as an oil.

¹H NMR (CDCl₃) δ: 3.64-3.46 (2H, m), 3.33 (1H, m), 3.19 (2H, d), 3.02(1H, dd), 2.49 (1H, m), 2.07 (1H, m), 1.65 (1H, m), 1.46 (9H, s).

Intermediate 27 Methyl(1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 21 startingfrom methyl(1aR,7bS)-5-{4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 28), as an off-white foam.

LCMS (Method D) r/t 2.50 and 2.62 (M+H) 461.

Intermediate 28 Methyl(1aR,7bS)-5-{4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylchloride (Intermediate 29, 0.6 g) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.352 g) in pyridine (3 mL) and DCM (3 mL) was left tostand at room temperature for 20 hours. The volatiles were removed byevaporation and the residue was partitioned between DCM and 2M aqueoushydrochloric acid. The organic layer was dried through a phase separatorand concentrated in vacuo. The residue was purified by chromatography onsilica, eluting with a mixture of ethyl acetate and cyclohexane, with agradient of 0-30%, to give methyl(1aR,7bS)-5-{4-fluoro-2-[(S)-1-(trifluoroacetyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.806 g) as a white foam.

LCMS (Method D) r/t 4.15 and 4.21 (M+Na) 579.

Intermediate 294-Fluoro-2-((S)-1-trifluoroacetylpyrrolidin-3-ylmethyl)benzenesulfonylchloride

Prepared by proceeding in a similar manner to Intermediate 23 startingfrom 2,2,2-trifluoro-1-[(S)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone(Intermediate 30), as a colourless, viscous gum.

LCMS (Method D) r/t 4.16 (M+H) 374.

Intermediate 302,2,2-Trifluoro-1-[(S)-3-(3-fluorobenzyl)pyrrolidin-1-yl]ethanone

Prepared by proceeding in a similar manner to Intermediate 24 startingfrom tert-butyl (S)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate(Intermediate 31), as a colourless oil.

LCMS (Method D) r/t 4.04 (M+H) 276.

Intermediate 31 tert-Butyl(S)-3-(3-fluorobenzyl)pyrrolidine-1-carboxylate

Prepared by proceeding in a similar manner to Intermediate 25 startingfrom tert-butyl (S)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate32).

¹H NMR (CDCl₃) δ: 7.27 (1H, m), 6.97-6.83 (3H, m), 3.46 (2H, m), 3.25(1H, m), 2.98 (1H, m), 2.67 (2H, m), 2.40 (1H, m), 1.91 (1H, m), 1.58(1H, m), 1.45 (9H, s).

Intermediate 32 tert-Butyl (3S)-3-iodomethylpyrrolidine-1-carboxylate

Prepared by proceeding in a similar manner to Intermediate 26 startingfrom tert-butyl (S)-3-hydroxymethylpyrrolidine-1-carboxylate.

¹H NMR (CDCl₃) δ: 3.59 (1H, dd), 3.51 (1H, m), 3.33 (1H, m), 3.19 (2H,d), 3.02 (1H, dd), 2.49 (1H, m), 2.07 (1H, m), 1.65 (1H, m), 1.46 (9H,s).

Intermediate 33 Methyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate(Intermediate 21, 0.138 g) and 2,2-dimethyloxirane (0.27 mL) in methanol(3 mL) was irradiated in the microwave at 100° C. for 3 hours. Aftercooling, the volatiles were removed by evaporation and the residue waspurified by chromatography on silica, eluting with a mixture of methanoland ethyl acetate, with a gradient of 0-20%, to give methyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.14 g).

LCMS (Method B) r/t 2.44 (M+H) 533.

Intermediate 34 Methyl(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Pyridine (1 mL) was added to a mixture of2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride(Intermediate 35, 0.11 g) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.17 g) in DCM (4 mL) and the mixture was stirred atroom temperature for 30 minutes. The mixture was partitioned between DCMand a saturated aqueous solution of sodium bicarbonate. The aqueousphase was extracted with further DCM and the combined organic layerswere dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuoand the resultant residue was purified by chromatography on silica,eluting with a mixture of 2M ammonia in methanol and DCM, with agradient of 0-20%, to give methyl(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.053 g) as a waxy solid.

LCMS (Method B) r/t 2.44 (M+H) 501.

Intermediate 352-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonyl chloride

Chlorosulphonic acid (1.7 mL) was added dropwise to a solution of3-(3-fluorobenzyl)-1-azabicyclo[2.2.2]octane (Intermediate 36, 0.56 g)in DCE (8 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutesand at 20° C. for 30 minutes. The mixture was then poured into a mixtureof ice and water and extracted with DCM. The combined organic layerswere washed with a saturated aqueous solution of sodium bicarbonate,dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo togive 2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluorobenzenesulfonylchloride (180 mg) as a gum.

LCMS (Method A) r/t 0.26 (M+H) 318.

Intermediate 36 3-(3-Fluorobenzyl)-1-azabicyclo[2.2.2]octane

A mixture of E and Z isomers of3-(3-fluorobenzylidene)-1-azabicyclo[2.2.2]octane (Intermediate 37, 0.56g) and palladium on carbon (0.1 g) in IMS (20 mL) was stirred at roomtemperature under an atmosphere of hydrogen for 16 hours. The mixturewas filtered and the filtrate was concentrated in vacuo to give3-(3-fluorobenzyl)-1-azabicyclo[2.2.2]octane (560 mg) as a colourlessoil.

¹H NMR (CDCl₃) δ: 7.26-7.19 (1H, m), 6.95-6.83 (3H, m), 3.10-3.01 (1H,m), 2.95-2.73 (4H, m), 2.72-2.58 (2H, m), 2.47-2.39 (1H, m), 2.02-1.87(1H, m), 1.85-1.75 (1H, m), 1.66-1.55 (2H, m), 1.53-1.37 (2H, m).

Intermediate 37 3-(3-Fluorobenzylidene)-1-azabicyclo[2.2.2]octane(mixture of E and Z isomers)

To a suspension of sodium hydride (0.50 g) in DME (16 mL) was added asolution of diethyl 3-fluorobenzylphosphonate (Intermediate 38, 1.52 g)in DME (5 mL) at 20° C. under an atmosphere of nitrogen. The mixture wasstirred for 30 minutes then 1-aza-bicyclo[2.2.2]octan-3-one (1.0 g) wasadded in a single portion. The mixture was stirred and heated at 60° C.for 30 minutes and then left to stand at room temperature for 16 hours.The mixture was partitioned between water and ethyl acetate and theaqueous phase was extracted with DCM. The combined organic layers werewashed with brine, dried (Na₂SO₄) and filtered. The filtrate wasevaporated to dryness and the residue was purified by chromatography onsilica, eluting with a mixture of 2M ammonia in methanol and DCM, with agradient of 0-10%, to give3-(3-fluorobenzylidene)-1-azabicyclo[2.2.2]octane as a mixture of E andZ isomers (1.13 g) as a colourless oil.

LCMS (Method A) r/t 0.27 and 1.87 (M+H) 218.

Intermediate 38 Diethyl 3-fluorobenzylphosphonate

A mixture of 3-fluorobenzyl bromide (2 g) and triethyl phosphite (2.2mL) was heated at 160° C. under an atmosphere of nitrogen for 4 hours.After cooling, the volatiles were removed in vacuo and the residue waspurified by chromatography on silica, eluting with a mixture of ethylacetate and cyclohexane, with a gradient of 0-100%, to give diethyl3-fluorobenzylphosphonate (2.46 g).

¹H NMR (CDCl₃) δ: 7.31-7.22 (1H, m), 7.11-6.89 (3H, m), 4.09-3.97 (4H,m), 3.13 (2H, d), 1.25 (6H, t).

Intermediate 39 Methyl(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(mixture of E and Z isomers)

A mixture of2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylchloride (mixture of E and Z isomers, Intermediate 40, 0.26 g), methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.41 g) and pyridine (1 mL) in DCM (4 mL) was stirredat room temperature for 17 hours. The mixture was partitioned betweenDCM and a saturated aqueous solution of sodium bicarbonate and theaqueous phase was extracted with further DCM. The combined organiclayers were dried (Na₂SO₄) and filtered and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography onsilica, eluting with a mixture of 2M ammonia in methanol and DCM, with agradient of 0-10%, to give methyl(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylateas a mixture of E and Z isomers (0.1 g) as a white solid.

LCMS (Method A) r/t 2.34 (M+H) 499.

Intermediate 402-(1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylchloride (mixture of E and Z isomers)

Prepared by proceeding in a similar manner to Intermediate 35, startingfrom 3-(3-fluorobenzylidene)-1-azabicyclo[2.2.2]octane (mixture of E andZ isomers), Intermediate 37).

LCMS (Method A) r/t 2.02 and 2.07 (M+H) 316.

Intermediate 41 Methyl(1aR,7bS)-5-{2-[(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(mixture of E and Z isomers)

To a solution of tert-butyl3-[5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)benzylidene]piperidine-1-carboxylate(mixture of E and Z isomers, Intermediate 42, 0.5 g) in DCM (8 mL) wasadded TFA (8 mL) and the mixture was stirred for 30 minutes. Thevolatiles were removed by evaporation and the residue was azeotropedwith toluene. The residue was dissolved in DCM (8 mL) and cooled to 0°C. Acetaldehyde (0.1 mL) was added followed by sodiumtriacetoxyborohydride (0.371 g) and the reaction mixture was allowed towarm slowly to room temperature and stirred for 1 hour. The mixture waspartitioned between DCM and 1M aqueous sodium hydroxide solution and theorganic layer was washed with water, and brine, dried (Na₂SO₄) andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by chromatography on silica, eluting with a mixture of 2Mammonia in methanol and DCM, with a gradient of 0-10%, to give methyl(1aR,7bS)-5-{2-[(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylateas a mixture of E and Z isomers (0.372 g).

LCMS (Method E) r/t 2.41 and 2.51 (M+H) 501.

Intermediate 42 tert-Butyl3-[5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)benzylidene]piperidine-1-carboxylate(mixture of E and Z isomers)

Prepared by proceeding in a similar manner to Intermediate 39, startingfrom tert-butyl3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate(mixture of E and Z isomers, Intermediate 43) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 8A).

LCMS (Method E) r/t 4.38 and 4.51 (M+H) 573.

Intermediate 43 tert-Butyl3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate(mixture of E and Z isomers)

n-Butyllithium (2.5M in hexanes, 0.226 mL) was added dropwise to asolution of tert-butyl3-(2-bromo-5-fluorobenzylidene)piperidine-1-carboxylate (mixture of Eand Z isomers, Intermediate 44, 0.2 g) in anhydrous THF (2 mL) under anatmosphere of argon at −70° C. Stirring was continued at −70° C. for 30minutes then sulfur dioxide was bubbled through the solution for 5minutes at −70° C. The mixture was stirred at −70° C. for 30 minutes andthen slowly warmed to room temperature. The volatiles were removed byevaporation and the residue was dissolved in DCM (10 mL) and cooled to−10° C. Sulfuryl chloride (0.044 mL) was added and the mixture wasallowed to warm slowly to room temperature. Stirring was continued for30 minutes and then the mixture was purified by chromatography onsilica, eluting with a mixture of TBME and cyclohexane, with a gradientof 0-30%, to give tert-butyl3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate as amixture of E and Z isomers (0.08 g).

LCMS (Method E) r/t 4.36 (M-tBu) 334.

Intermediate 44 tert-Butyl3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate(mixture of E and Z isomers)

Sodium hydride (60% in mineral oil, 0.404 g) was added portionwise to astirred solution of diethyl (2-bromo-5-fluorobenzyl)phosphonate (2.98 g)and tert-butyl 3-oxo-piperidine-1-carboxyate (1.83 g) in DME (50 mL) atroom temperature and stirring was continued for 18 hours. The reactionmixture was combined with a second batch obtained in a similar mannerstarting from of diethyl (2-bromo-5-fluoro-benzyl)phosphonate (3.22 g)and the combined mixture was treated with water then extracted withdiethyl ether. The organic layer was washed with brine, dried (Na₂SO₄)and filtered and the filtrate was concentrated in vacuo. The residue waspurified by chromatography on silica, eluting with a mixture of TBME andcyclohexane, with a gradient of 0-20%, to give tert-butyl3-(2-chlorosulfonyl-5-fluorobenzylidene)piperidine-1-carboxylate as amixture of E and Z isomers (1.18 g).

LCMS (Method B) r/t 4.52 (M+H) 370.

Intermediate 45 Methyl(1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride(Intermediate 46, 0.21 g) was added to a solution of methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.290 g) in DCM (10 mL) and pyridine (2 mL) and themixture was stirred at room temperature for 4 hours. The mixture wasevaporated to dryness and the residue was partitioned between DCM andwater. The organic layer was dried (Na₂SO₄), filtered and the filtratewas concentrated in vacuo. The residue was purified by chromatography onsilica, eluting with a mixture of 2M ammonia in methanol and DCM, with agradient of 0-15%, to give methyl(1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(0.071 g).

¹H NMR (CDCl₃) δ: 7.95-7.88 (1H, m), 7.21-7.15 (1H, m), 7.03-6.86 (3H,m), 4.31 (1H, d), 3.81-3.73 (4H, m), 2.89-2.63 (4H, m), 2.39-2.28 (2H,m), 2.09-2.08-1.95 (1H, m), 1.94-1.44 (8H, m), 1.06-0.94 (6H, m).

Intermediate 46 2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylchloride

A solution of 1-ethyl-3-(3-fluorobenzyl)piperidine (Intermediate 47,0.214 g) in DCE (1 mL) was added to chlorosulfonic acid (2 mL) at 0° C.The mixture was allowed to warm to room temperature and stirred for 2hours. The mixture was then added dropwise to a mixture of ice and brineand extracted with DCM. The organic layer was dried (Na₂SO₄) andfiltered and the filtrate was evaporated to dryness to give2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.44g) as a solid.

¹H NMR (CDCl₃) δ: 8.17-8.11 (1H, m), 7.43-7.37 (1H, m), 7.19-7.12 (1H,m), 3.62-3.52 (1H, m), 3.42-3.32 (1H, m), 3.16 (2H, d), 3.11-2.92 (3H,m), 2.64-2.29 (3H, m), 1.91 (2H, d), 1.43 (3H, t), 1.39-1.23 (1H, m).

Intermediate 47 1-Ethyl-3-(3-fluorobenzyl)piperidine

A solution of lithium aluminium hydride (2M in THF, 2.8 mL) was addeddropwise to a solution of 1-[3-(3-fluorobenzyl)piperidin-1-yl]ethanone(Intermediate 48, 0.66 g) in anhydrous THF (20 mL) at 0° C. under argon.The mixture was stirred for 30 minutes then allowed to warm to roomtemperature and stirred for 2 hours. The mixture was recooled to 0° C.,water was added and the mixture was extracted with ether, washed withbrine, dried (Na₂SO₄) and filtered. The filtrate was evaporated todryness to give 1-ethyl-3-(3-fluorobenzyl)piperidine (0.535 g).

¹H NMR (CDCl₃) δ: 7.25-7.17 (1H, m), 6.95-6.80 (3H, m), 2.92-2.73 (2H,m), 2.58-2.42 (2H, m), 2.42-2.26 (2H, m), 1.96-1.76 (2H, m), 1.74-1.48(4H, m), 1.04 (3H, t), 1.00-0.84 (1H, m).

Intermediate 48 1-[3-(3-Fluorobenzyl)piperidin-1-yl]ethanone

A mixture of 1-[3-(3-fluorobenzylidene)piperidin-1-yl]ethanone (mixtureof E and Z isomers, Intermediate 49, 0.7 g), palladium hydroxide (20% oncarbon, 0.07 g) in ethyl acetate (20 mL) and IMS (1 mL) was degassed bynitrogen/vacuum purging. The reaction mixture was stirred under anatmosphere of hydrogen for 21.5 hours and then filtered. The filtratewas evaporated to dryness to give1-[3-(3-fluorobenzyl)piperidin-1-yl]ethanone (0.66 g).

¹H NMR (CDCl₃) δ: 7.31-7.17 (1H, m), 6.97-6.80 (3H, m), 4.52-4.43 (0.5H,m), 4.41-4.31 (0.5H, m), 3.76-3.65 (0.5H, m), 3.65-3.55 (0.5H, m),3.07-2.95 (0.5H, m), 2.82-2.62 (1.5H, m), 2.60-2.49 (1H, m), 2.45-2.33(1H, m), 2.08 (1.5H, s), 1.95 (1.5H, s), 1.83-1.63 (3H, m), 1.50-1.32(1H, m), 1.29-1.09 (1H, m).

Intermediate 49 1-[3-(3-Fluorobenzylidene)piperidin-1-yl]ethanone(mixture of E and Z isomers)

Acetyl chloride (0.515 mL) was added to a mixture of3-(3-fluorobenzylidene)piperidine (mixture of E and Z isomers,Intermediate 50, 1.5 g) and N,N-di-isopropyl-N-ethylamine (2.52 mL) inanhydrous THF (50 mL) at 0° C. under nitrogen. The mixture was allowedto warm to room temperature and stirred for 2 hours. The mixture wasdiluted with water (100 mL) and extracted with ether, washed with brine,dried (Na₂SO₄) and filtered. The filtrate was evaporated to dryness andthe residue was purified by chromatography on silica, eluting with amixture of ethyl acetate and cyclohexane, with a gradient of 75-100%, togive 1-[3-(3-fluorobenzylidene)piperidin-1-yl]ethanone as a mixture of Eand Z isomers (1.38 g). ¹H NMR (CDCl₃) δ: 7.37-7.21 (1H, m), 7.04-6.82(3H, m), 6.48-6.26 (1H, 4s), 4.39-4.00 (2H, m), 3.72-3.48 (2H, m),2.61-2.41 (2H, m), 2.18-2.02 (3H, 4s), 1.83-1.61 (2H, m).

Intermediate 50 3-(3-Fluorobenzylidene)piperidine hydrochloride mixtureof E and Z isomers

A solution of HCl in dioxane (4M, 30 mL) was added to a solution oftert-butyl 3-(3-fluorobenzylidene)piperidine-1-carboxylate (mixture of Eand Z isomers, Intermediate 51, 2.38 g) in diethyl ether (30 mL) and themixture was stirred at room temperature for 5 hours. The mixture wasconcentrated in vacuo and the residue was treated with diethyl ether.The solid was collected by filtration, washed with diethyl ether anddried in vacuo to give 3-(3-fluorobenzylidene)piperidine hydrochlorideas a mixture of E and Z isomers (1.64 g).

¹H NMR (CDCl₃) 3:2 ratio of E and Z isomers δ: 9.34 (2H, br s),7.48-7.37 (1H, m), 7.22-7.00 (3H, m), 6.59 (1H, s), 3.78-3.68 (2H, m),3.13 (2H, m), 2.52 (1.2H, m), 2.43 (0.8H, m), 1.84 (1.2H, m), 1.76(0.8H, m).

Intermediate 51 tert-Butyl3-(3-fluorobenzylidene)piperidine-1-carboxylate (mixture of E and Zisomers)

(3-Fluorobenzyl)(triphenyl)phosphonium bromide (Intermediate 52, 5.3 g)was added in portions to a solution of sodium tert-butoxide (1.06 g) inanhydrous THF (20 mL) at room temperature and the resultant mixture wasstirred for 30 minutes. A solution of tert-butyl3-oxopiperidine-1-carboxylate (2 g) in anhydrous THF (10 mL) was addeddropwise at room temperature and the mixture was stirred for 24 hours.The mixture was diluted with water and extracted with ether, washed withbrine, dried (Na₂SO₄) and filtered. The filtrate was concentrated invacuo and the residue was purified by chromatography on silica, elutingwith a mixture of ethyl acetate and cyclohexane, with a gradient of0-20%, to give tert-butyl3-(3-fluorobenzylidene)piperidine-1-carboxylate as a 3:2 mixture of Eand Z isomers (1.42 g).

¹H NMR (CDCl₃) δ: 7.33-7.21 (1H, m), 7.05-6.85 (3H, m), 6.37 (0.6H, s),6.28 (0.4H, s), 4.16 (0.8H, s), 4.00 (1.2H, s), 3.50 (2H, t), 2.50(1.2H, m), 2.39 (0.8H, m), 1.72 (0.8H, m), 1.62 (1.2H, m), 1.48 (5.4H,s), 1.34 (3.6H, br s).

Intermediate 52 (3-Fluorobenzyl)(triphenyl)phosphonium bromide

A mixture of 3-fluorobenzyl bromide (5 g) and triphenyl phosphine (6.94g) in toluene (50 mL) was heated at reflux for 3 hours. After cooling,the solid was collected by filtration, washed with toluene and driedunder vacuum at 50° C. to give (3-fluorobenzyl)(triphenyl)phosphoniumbromide (10.1 g).

¹H NMR (DMSO-d₆) δ: 7.96-7.87 (3H, m), 7.81-7.64 (12H, m), 7.35-7.26(1H, m), 7.20-7.11 (1H, m), 6.88-6.82 (1H, m), 6.78-6.70 (1H, m), 5.21(2H, d).

Intermediate 53 Methyl(1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 88, startingfrom 2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylchloride (Intermediate 54) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A) as a glass.

LCMS (Method A) r/t 2.34 and 2.42 (M+H) 503.

Intermediate 542-[2-((S)-1-Ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonyl chloride

Prepared by proceeding in a similar manner to Intermediate 35, startingfrom (S)-1-ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (Intermediate55), as an oil.

¹H NMR (CDCl₃) δ: 8.10 (1H, dd), 7.42 (1H, d), 7.13 (1H, t), 3.97-3.84(1H, m), 3.47-3.19 (3H, m), 3.17-2.80 (3H, m), 2.48-2.21 (3H, m),2.16-1.96 (3H, m), 1.54-1.41 (3H, m).

Intermediate 55 (S)-1-Ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine

Lithium aluminium hydride (2M in THF, 1.42 mL) was added to a solutionof 1-{(S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidin-1-yl}ethanone(Intermediate 56, 0.19 g) in THF (7 mL) at room temperature under anatmosphere of nitrogen. The mixture was heated at 60° C. for 2 hoursthen allowed to cool to room temperature and carefully treated withwater (0.15 mL) followed by 4M sodium hydroxide solution (0.15 mL) andthen water (0.36 mL) at 0° C. Anhydrous sodium sulfate was added and thesuspension was diluted with ether and filtered through Celite. Thefiltrate was concentrated in vacuo to give(S)-1-ethyl-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (0.15 g) as an oil.

LCMS (Method A) r/t 1.73 (M+H) 222.

Intermediate 561-{(S)-2-[2-(3-Fluorophenyl)ethyl]pyrrolidin-1-yl}ethanone

A mixture of (S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (Intermediate57, 0.167 g) and acetyl chloride (0.123 mL) in DCM (5 mL) was stirred atroom temperature for 1.5 hours. The resultant solution was washed with1M hydrochloric acid, dried (Na₂SO₄) and filtered. The filtrate wasconcentrated in vacuo to give1-{(S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidin-1-yl}ethanone (0.19 g) asan oil.

¹H NMR (CDCl₃) δ: 7.29-7.17 (1H, m), 7.01-6.81 (3H, m), 3.49-3.35 (2H,m), 2.75-2.50 (2H, m), 2.23-2.12 (1H, m), 2.06-1.83 (7H, m), 1.82-1.68(1H, m), 1.64-1.49 (1H, m).

Intermediate 57 (S)-2-[2-(3-Fluorophenyl)ethyl]pyrrolidine

A solution of tert-butyl(S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine-1-carboxylate (Intermediate58, 0.307 g) in DCM (5 mL) was treated with TFA (5 mL) and the mixturewas stirred at room temperature for 1 hour. The volatiles were removedby evaporation and the residue was dissolved in acetonitrile andpurified by SCX cartridge. The cartridge was washed with acetonitrilefollowed by methanol and the product was eluted with 2M ammonia inmethanol to give (S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine (0.167 g) asan oil.

¹H NMR (CDCl₃) δ: 7.27-7.19 (1H, m), 6.98 (1H, d), 6.95-6.83 (2H, m),3.07-2.95 (2H, m), 2.90-2.82 (1H, m), 2.79-2.57 (2H, m), 1.97-1.65 (6H,m), 1.39-1.25 (1H, m).

Intermediate 58 tert-Butyl(S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine-1-carboxylate

A solution of tert-butyl(R)-2-[(E)-2-(2-bromo-5-fluorophenyl)ethenyl]pyrrolidine-1-carboxylate(Intermediate 59, 0.37 g) in ethanol (20 mL) was treated with 10%palladium on carbon (0.1 g) and the mixture was stirred at roomtemperature under an atmosphere of hydrogen for 36 hours. The mixturewas diluted with isopropanol and filtered through Celite and thefiltrate was evaporated to dryness to give tert-butyl(S)-2-[2-(3-fluorophenyl)ethyl]pyrrolidine-1-carboxylate (0.307 g).

LCMS (Method A) r/t 4.26 (M-tBu) 238.

Intermediate 59 tert-Butyl(R)-2-[(E)-2-(2-bromo-5-fluorophenyl)ethenyl]pyrrolidine-1-carboxylate

A solution of diethyl (2-bromo-5-fluorobenzyl)phosphonate (0.325 g) andtert-butyl (R)-2-formylpyrrolidine-1-carboxylate (0.2 g) in anhydrousTHF (5 mL) was treated with sodium hydride (60% dispersion in mineraloil, 0.048 g). The mixture was stirred at room temperature for 2 hours,then diluted with water and extracted with ether. The organic layer wasdried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuoto give tert-butyl(R)-2-[(E)-2-(2-bromo-5-fluorophenyl)ethenyl]pyrrolidine-1-carboxylate(0.37 g) as an oil.

¹H NMR (CDCl₃) δ: 7.56-7.45 (1H, m), 7.23-1.16 (1H, m), 6.89-6.78 (1H,m), 6.71 (1H, d), 6.08 (1H, br s), 3.80-3.73 (1H, m), 3.54-3.43 (2H, m),2.00-1.73 (4H, m), 1.46 (9H, br s).

Intermediate 60 Methyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Tetra-n-butylammonium fluoride (1.0M in THF, 0.65 mL) was added to asolution of methyl(1aR,7bS)-5-{(2-[(R)-1-(2-tert-butyldimethylsilyloxyethyl)pyrrolidin-3-ylmethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 61, 0.14 g) in THF (5 mL) at room temperature under anatmosphere of nitrogen and stirring was continued for 19 hours. Themixture was partitioned between ethyl acetate and water and the organiclayer was washed with brine, dried (Na₂SO₄) and filtered. The filtratewas concentrated in vacuo and the residue was purified by chromatographyon silica, eluting with a mixture of methanol and ethyl acetate, with agradient of 0-20%, to give methyl(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.034 g).

LCMS (Method B) r/t 2.33 (M+H) 505.

Intermediate 61 Methyl(1aR,7bS)-5-{(2-[(R)-1-(2-tert-butyldimethylsilyloxyethyl)-pyrrolidin-3-ylmethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Sodium triacetoxyborohydride (0.127 g) was added to a solution of methyl(1aR,7bS)-5-[(2-((R)-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 21, 0.138 g) and (tert-butyldimethylsilyloxy)acetaldehyde(0.105 g) in DCM (3 mL) and stirring was continued at room temperaturefor 22 hours. The mixture was diluted with DCM and the organic layer waswashed with water and brine, dried (Na₂SO₄) and filtered. The filtratewas concentrated in vacuo and the residue was purified by chromatographyon silica, eluting with a mixture of methanol and DCM, with a gradientof 0-10% followed by a mixture of ethyl acetate and cyclohexane, with agradient of 30-100% and finally by a mixture of methanol and ethylacetate, with a gradient of 0-20%, to give methyl(1aR,7bS)-5-{(2-[(R)-1-(2-tert-butyldimethylsilyloxyethyl)-pyrrolidin-3-ylmethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.138 g) as a pale yellow foam. LCMS (Method D) r/t 3.37 (M+H) 619.

Intermediate 62 Methyl(1aR,7bS)-5-[2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 34, startingfrom,2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-ylmethyl)-4-fluorobenzenesulfonylchloride (Intermediate 63) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A).

LCMS (Method A) r/t 2.87 and 2.91 (M+H) 529.

Intermediate 632-(8-Ethyl-8-azabicyclo[3.2.1]oct-3-ylmethyl)-4-fluorobenzenesulfonylchloride

Chlorosulphonic acid (0.43 mL) was added dropwise to a solution of8-ethyl-3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane (Intermediate 64,0.161 g) in DCE (2 mL) at 0° C. The mixture was stirred at 0° C. for 15minutes and then poured into a mixture of ice and water. The aqueousphase was extracted with DCM and the combined organic layers were dried(Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to give2-(8-ethyl-8-azabicyclo[3.2.1]oct-3-ylmethyl)-4-fluorobenzenesulfonylchloride (0.115 g) as a foam. LCMS (Method A) r/t 2.55 and 2.73 (M+H)346.

Intermediate 64 8-Ethyl-3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane

Ethyl iodide (0.11 mL) was added to a mixture of3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane (Intermediate 65, 0.31 g)and potassium carbonate (0.19 g) in DMF (3 mL) and stirring wascontinued at room temperature for 3 days. The volatiles were removed byevaporation and the residue was purified by SCX cartridge. The cartridgewas washed with methanol and the product was eluted with 2M ammonia inmethanol. The residue was purified by chromatography on silica, elutingwith a mixture of 2M ammonia in methanol and DCM, with a gradient of0-10%, to give 8-ethyl-3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane(0.166 g) as a brown oil.

LCMS (Method A) r/t 2.49 (M+H) 248.

Intermediate 65 3-(3-Fluorobenzyl)-8-azabicyclo[3.2.1]octane

A mixture of benzyl3-(3-fluorobenzylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate(Intermediate 66, 0.522 g) and 10% palladium on carbon (0.1 g) inethanol (40 mL) was stirred under an atmosphere of hydrogen for 16hours. The mixture was filtered and the filtrate was concentrated invacuo. The resultant oil was dissolved in ethanol (40 mL), treated with10% palladium on carbon (0.1 g) and stirred under an atmosphere ofhydrogen for 48 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo to give3-(3-fluorobenzyl)-8-azabicyclo[3.2.1]octane (0.315 g) as a colourlessoil.

LCMS (Method B) r/t 0.26, 0.37 and 2.05 (M+H) 220.

Intermediate 66 Benzyl3-(3-fluorobenzylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate

Diethyl 3-fluorobenzylphosphonate (Intermediate 38, 1.5 g) in DME (10mL) was added dropwise to a stirred suspension of sodium hydride (60% inmineral oil, 0.24 g) in DME (15 mL) at room temperature and theresultant mixture was stirred under an atmosphere of nitrogen at roomtemperature for 30 minutes. Benzyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.58 g) in DME (10 mL)was then added and stirring was continued for 16 hours. The mixture waspartitioned between ethyl acetate and water and the aqueous phase wasextracted with further ethyl acetate. The combined organic layers weredried (Na₂SO₄) and filtered and the filtrate was concentrated in vacuo.The residue was purified by chromatography on silica, eluting with amixture of ethyl acetate and cyclohexane, with a gradient of 0-60%, togive benzyl3-(3-fluorobenzylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.5 g)as a colourless oil which solidified on standing.

LCMS (Method A) r/t 4.40 (M+H) 352.

Intermediate 67 Methyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methyl-pyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methane sulfonic anhydride (0.159 g) was added to a stirred, cooledmixture of methyl(1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 68, 0.3 g) and N,N-diisopropyl-N-ethylamine (0.237 g) inDCM (30 mL) at 0° C. The resulting solution was stirred for 15 minutesat 0-5° C. then 3-methylpyrrolidin-3-ol (0.124 g) was added and stirringwas continued at room temperature for 18 hours. The mixture was quenchedby addition of water and the mixture was extracted with DCM. The organicphase was dried (Na₂SO₄) and filtered and the filtrate was concentratedin vacuo to give methyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]-benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.34 g) as a yellow solid.

The compound was used without further characterization.

Intermediate 68 Methyl(1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

A mixture of methyl(1aR,7bS)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 69, 5.0 g), (Z)-3-(tributylstannanyl)prop-2-en-1-ol(Intermediate 70, 5.06 g), tris-(dibenzylideneacetone)dipalladium (0.89g) and tri-tert-butylphosphonium tetrafluoroborate (0.56 g) in dioxane(50 mL) and DMSO (5 mL) was stirred at room temperature for 1 hour. Themixture was quenched by the addition of 5 mL of saturated aqueoussolution of sodium bicarbonate and the mixture was extracted with ethylacetate, washed with water, dried (Na₂SO₄) and filtered. The filtratewas evaporated to dryness and the residue was purified by chromatographyon silica, eluting with a mixture of ethyl acetate and petroleum ether,with a gradient of 30-50%, to give methyl(1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(4.5 g) as an off-white solid.

¹H NMR (CDCl₃) δ: 8.19 (1H, m), 7.39 (1H, d), 7.16 (1H, m), 7.02 (1H,m), 6.96 (2H, m), 6.03 (1H, m), 4.41 (1H, m), 4.23 (2H, m), 3.88 (1H,dd), 3.71 (3H, 2s), 3.65 (3H, 2s), 2.06 (1H, m), 1.82 (1H, m), 1.25 (1H,m), 1.14 (1H, m).

Intermediate 69 Methyl(1aR,7bS)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

To a solution of methyl(1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 6, 6.0 g) in THF (60 mL) under an atmosphere of nitrogenwas added sodium hydride (60% oil dispersion, 1.05 g) in severalbatches. The resulting solution was stirred at room temperature for 30minutes then methyl chloroformate (2.49 g) was added dropwise and thesolution was stirred at room temperature overnight. A saturated aqueoussolution of sodium bicarbonate was added and the mixture was dilutedwith water and extracted with ethyl acetate. The organic phase was dried(Na₂SO₄) and filtered and the filtrate was concentrated in vacuo. Theresidue was triturated with hexane and the solid was collected byfiltration to give methyl(1aR,7bS)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(6.4 g) as a yellow solid.

¹H NMR (CDCl₃) δ: 8.42 (1H, m), 7.48 (1H, dd), 7.37 (1H, d), 7.19 (2H,m), 4.42 (1H, m), 3.95 (1H, dd), 3.86 (3H, s,), 3.69 (3H, s), 2.06 (1H,m), 1.84 (1H, m), 1.16 (2H, m).

Intermediate 70 (Z)-3-(tributylstannanyl)prop-2-en-1-ol

Propargyl alcohol (5 mL) was added to a solution of lithium aluminiumhydride (1M in THF, 43 mL) in THF (70 mL) at −78° C. The resultantmixture was warmed to room temperature, stirred for 18 hours and thenre-cooled to −78° C. A solution of tri-n-butyl tin chloride (8.32 mL) indiethyl ether (50 mL) was added and stirring was continued for 3 hourswhile the mixture gradually warmed to room temperature. The mixture wascooled to −5° C. and quenched by addition of water and 15% aqueoussodium hydroxide solution then it was warmed to room temperature. Ethylacetate was added and the mixture was stirred for 1 hour then filteredthrough Celite. The filtrate was evaporated to dryness and the residuewas purified by chromatography on a silica column which had beenpre-washed with 20% triethylamine in acetonitrile. The column was elutedwith a mixture of ethyl acetate and pentane, with a gradient of 0-10%,to give (Z)-3-(tributylstannanyl)prop-2-en-1-ol (5.06 g) as a clear oil.

¹H NMR (CDCl₃) δ: 6.70 (1H, dt), 6.08 (1H, dt), 4.12 (2H, dd), 1.49 (6H,m), 1.31 (6H, m), 0.98-0.84 (15H, m).

Intermediate 71 Methyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enylbenzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 67, startingfrom methyl(1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 68) and piperidin-4-ol, as a yellow solid.

The compound was used without further characterization.

Intermediate 72 Methyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enylbenzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 67, startingfrom methyl(1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 68) and 4-methylpiperidin-4-ol, as a yellow solid.

The compound was used without further characterization.

Intermediate 73 Methyl(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of 3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane(Intermediate 74, 0.299 g) in DCE (3 mL) was added dropwise to a mixtureof chlorosulphonic acid (0.871 mL) in DCE (3 mL) at −10° C. Stirring wascontinued at −10° C. for 1 hour, then the mixture was allowed to warm toroom temperature slowly and then stirred for 1 hour. The mixture wasdiluted with DCM and added carefully to a mixture of ice, water andsodium bicarbonate (3.3 g). The mixture was extracted with DCM followedby TBME. The combined organic layers were dried (Na₂SO₄) and filteredand the filtrate was concentrated in vacuo. The residue was dissolved inDCM (3 mL) and added to a solution of methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.266 g) in pyridine (2 mL) and DCM (6 mL) and themixture was stirred at room temperature for 20 hours. The volatiles wereremoved by evaporation and the residue was purified by chromatography onsilica, eluting with a mixture of methanol and ethyl acetate, with agradient of 0-20%, to give methyl(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.187 g) as a yellow solid.

LCMS (Method E) r/t 2.31 (M+H) 487.

Intermediate 74 3-Ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane

Lithium aluminium hydride (2M in THF, 5 mL) was added dropwise to asolution of 3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one(Intermediate 75, 0.659 g) in anhydrous THF (20 mL) at 0° C. under anatmosphere of nitrogen. The mixture was allowed to warm to roomtemperature and then heated at reflux for 4 hours. After cooling in anice bath, the mixture was treated with water and then extracted withdiethyl ether, washed with brine, dried (Na₂SO₄) and filtered. Thefiltrate was concentrated in vacuo to give3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexane (0.529 g) as anoil.

LCMS (Method E) r/t 1.45 (M+H) 206.

Intermediate 753-Ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one

A mixture of ethyl2-chloromethyl-3-(3-fluorophenyl)cyclopropanecarboxylate, (Intermediate76, 1 g) and ethylamine (70% in water, 5 mL) in IMS (5 mL) was heated ina sealed vial at 95° C. for 18 hours. After cooling, the volatiles wereremoved by evaporation and the residue was partitioned between ethylacetate and water. The organic layer was dried (Na₂SO₄) and filtered andthe filtrate was concentrated in vacuo. The residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 0-100%, to give3-ethyl-6-(3-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (0.659 g) as awhite solid.

LCMS (Method E) r/t 2.97 (M+H) 220.

Intermediate 76 Ethyl2-chloromethyl-3-(3-fluorophenyl)cyclopropanecarboxylate

A solution of ethyl diazoacetate (9.66 g) in DCM (20 mL) was addeddropwise over 7 hours via syringe pump to a mixture of1-((E)-3-chloroprop-1-enyl)-3-fluorobenzene (Intermediate 77, 5.16 g)and rhodium acetate dimer (0.2 g) in DCM (30 mL) at room temperatureunder an atmosphere of argon and stirring was continued for 72 hours.The volatiles were removed by evaporation and the residue was purifiedby chromatography on silica, eluting with a mixture of DCM andcyclohexane, with a gradient of 0-25%, to give ethyl2-chloromethyl-3-(3-fluorophenyl)cyclopropanecarboxylate (4.27 g).

¹H NMR (CDCl₃) δ: 7.30-7.18 (1H, m), 6.97-6.75 (3H, m), 4.30-4.08 (2H,m), 4.01 (1H, dd), 3.85 (1H, dd), 2.67 (1H, t), 2.26-2.00 (2H, m), 1.30(3H, t).

Intermediate 77 1-((E)-3-Chloroprop-1-enyl)-3-fluorobenzene

Thionyl chloride (3 mL) was slowly added to a solution of(E)-3-(3-fluorophenyl)prop-2-en-1-ol (6.23 g) in diethyl ether (100 mL)at 0° C. The mixture was allowed to warm to room temperature and stirredfor 18 hours. Additional thionyl chloride (1.5 mL) was added andstirring was continued for 2 hours. Further thionyl chloride (3 mL) wasadded and stirring was continued for 2.5 hours. Pyridine (two drops) wasadded and stirring was continued for 18 hours. The mixture was carefullyquenched by addition of a saturated aqueous solution of sodiumbicarbonate and water. The organic layer was dried (Na₂SO₄) and filteredand the filtrate was concentrated in vacuo. The residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 0-35%, to give1-((E)-3-chloroprop-1-enyl)-3-fluorobenzene (7.49 g).

¹H NMR (CDCl₃) δ: 7.32-7.24 (1H, m), 7.16-7.04 (2H, m), 7.00-6.90 (1H,m), 6.61 (1H, d), 6.31 (1H, dt), 4.22 (2H, dd).

Intermediate 78 Methyl(1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of tert-butyl(S)-2-((Z)-2-{5-fluoro-2-[(1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl]phenyl}ethenyl)pyrrolidine-1-carboxylate(Intermediate 79, 0.436 g) in DCM (10 mL) was treated with TFA (8 mL)and the mixture was stirred at room temperature for 1.5 hours. Thevolatiles were removed by evaporation azeotroping with toluene. Theresidue was partitioned between a saturated aqueous solution of sodiumbicarbonate and DCM. The organic layer was dried (Na₂SO₄) and filteredand the filtrate was concentrated in vacuo to give methyl(1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(0.424 g) as a glass.

¹H NMR (CDCl₃) δ: 8.06-8.00 (1H, m), 7.14 (1H, d), 7.00-7.00 (2H, m),6.87-6.79 (2H, m), 5.87-5.80 (1H, m), 4.34 (1H, d), 3.86-3.75 (4H, m),3.10-3.01 (1H, m), 2.84-2.74 (1H, m), 1.93-1.42 (7H, m), 1.05-0.97 (2H,m).

Intermediate 79 tert-Butyl((S)-2-((Z)-2-{5-fluoro-2-[(1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl]phenyl}ethenyl)pyrrolidine-1-carboxylate

A mixture of methyl(1aR,7bS)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 6, 0.3 g), tert-butyl(S)-2-((Z)-2-tributylstannanylethenyl)pyrrolidine-1-carboxylate(Intermediate 80, 0.85 g), tris-(dibenzylideneacetone)dipalladium (0.026g) and tri-tert-butylphosphonium tetrafluoroborate (0.016 g) in dioxane(5 mL) and DMSO (0.5 mL) was degassed with a stream of argon and thenheated in a sealed vial at 85° C. for 2 hours. After cooling, themixture was diluted with ethyl acetate, filtered through Celite, washedwith water, dried (MgSO₄) and filtered. The filtrate was concentrated invacuo and the residue was purified by chromatography on silica, elutingwith a mixture of methanol and DCM, with a gradient of 0-10%, to givetert-butyl((S)-2-((Z)-2-{5-fluoro-2-[(1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl]phenyl}ethenyl)pyrrolidine-1-carboxylate(0.435 g) as a glass.

LCMS (Method F) r/t 3.89 (M+H) 573.

Intermediate 80 tert-Butyl(S)-2-((Z)-2-tributylstannanylethenyl)pyrrolidine-1-carboxylate

Bis-(cyclopentadienyl)zirconium(IV) chloride hydride (0.644 g) wassuspended in anhydrous THF (5 mL) and the mixture was degassed with astream of argon and then treated with tert-butyl(S)-2-(tributylstannanylethynyl)pyrrolidine-1-carboxylate (Intermediate81, 1.0 g). The mixture was stirred at room temperature for 2.25 hours,then additional bis-(cyclopentadienyl)zirconium(IV) chloride hydride(0.38 g) was added. Stirring was continued for a further 1.5 hours thenadditional bis-(cyclopentadienyl)zirconium(IV) chloride hydride (0.5 g)was added. After 1.5 hours stirring, the reaction mixture was treatedwith a saturated aqueous solution of sodium bicarbonate and extractedwith diethyl ether. The organic phase was dried (MgSO₄) and filtered.The filtrate was concentrated to dryness and the residue was purified bychromatography on silica, eluting with a mixture of TBME and pentane,with a gradient of 0-20%, to give tert-butyl(S)-2-((Z)-2-tributylstannanylethenyl)pyrrolidine-1-carboxylate (1.157g) as an oil.

¹H NMR (CDCl₃) δ: 6.44 (1H, dd), 5.85 (1H, br s), 3.96 (1H, br s),3.55-3.35 (2H, m), 2.12-1.97 (1H, m), 1.92-1.62 (3H, m), 1.55-1.45 (6H,m), 1.42 (9H, s), 1.38-1.25 (6H, m), 1.01-0.86 (15H, m).

Intermediate 81 tert-Butyl(S)-2-(tributylstannanylethynyl)pyrrolidine-1-carboxylate

A solution of tert-butyl (S)-2-ethynylpyrrolidine-1-carboxylate (3.25 g)in anhydrous THF (125 mL) was cooled to −78° C. under a nitrogenatmosphere and treated with n-butyllithium (2.5M in hexanes, 8 mL),whilst maintaining the internal temperature below −60° C. Stirring wascontinued at −60° C. for 10 minutes then the mixture was allowed to warmto 0° C. and stirred at that temperature for 2.5 hours. Tributyltinchloride (5.54 mL) was added and the mixture was allowed to warm to roomtemperature and stirred for 1.5 hours. The mixture was cooled to 0° C.and a saturated aqueous solution of sodium bicarbonate was added,followed by water. The mixture was extracted with ethyl acetate, dried(Na₂SO₄) and filtered. The filtrate was concentrated in vacuo and theresidue was purified by chromatography on silica, eluting with a mixtureof TBME and pentane, with a gradient of 0-30%, to give tert-butyl(S)-2-(tributylstannanylethynyl)pyrrolidine-1-carboxylate (4.09 g) as acolourless oil.

1H NMR (CDCl3) δ: 4.43 (1H, br s), 3.47 (1H, br s), 3.31 (1H, br s),2.16-1.94 (3H, m), 1.87 (1H, br s), 1.60-1.50 (6H, m), 1.49 (9H, s),1.40-1.29 (6H, m), 0.99-0.87 (15H, m).

Intermediate 82 Methyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethyl-pyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A mixture of methyl(1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 83, 0.3 g), N,N-diisopropyl-N-ethylamine (0.204 g) and(S)-pyrrolidin-3-ylmethanol (Intermediate 84, 0.107 g) in DCM (30 mL)was stirred at room temperature for 4 hours. Water was added and themixture was extracted with DCM. The combined organic layers were dried(Na₂SO₄) and filtered and the filtrate was concentrated in vacuo to givemethyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.38 g) as a yellow solid.

The compound was used without further characterization.

Intermediate 83 Methyl(1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Methane sulfonic anhydride (0.87 g) was added in several batches to astirred, cooled mixture of methyl(1aR,7bS)-5-{N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 68, 1.63 g) and N,N-diisopropyl-N-ethylamine (1.29 g) inDCM (40 mL) at 0° C. under an atmosphere of nitrogen. The resultingsolution was stirred at 0-5° C. for 1 hour then a saturated aqueoussolution of sodium bicarbonate was added. The mixture was extracted withDCM and the organic phase was dried (Na₂SO₄) and filtered. The filtratewas concentrated in vacuo and the residue was purified by chromatographyon silica, eluting with a mixture of ethyl acetate and petroleum ether,with a gradient of 25-33%, to give methyl(1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(1.8 g) of as an off-white solid.

The compound was used without further characterization.

Intermediate 84 (S)-Pyrrolidin-3-ylmethanol

Acetyl chloride (9 mL) was added dropwise at 0° C. to methanol (40 mL)under an atmosphere of nitrogen. The mixture was stirred for 0.5 hoursat 0° C. then tert-butyl (S)-3-hydroxymethylpyrrolidine-1-carboxylate(2.5 g) was added. The resulting solution was stirred at roomtemperature overnight then concentrated in vacuo. The residue wasdissolved in isopropanol (40 mL) and potassium carbonate (10 g) wasadded. The mixture was stirred at room temperature overnight thenfiltered. The filtrate was concentrated in vacuo to give(S)-pyrrolidin-3-ylmethanol (1.24 g) as a yellow oil.

The compound was used without further characterization.

Intermediate 85 Methyl(1aR,7bS)-5-(N-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethyl-pyrrolidin-1-yl)prop-1-enylbenzenesulfonyl}-N-(methoxycarbonyl)amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 82, startingfrom methyl(1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 83) and (R)-pyrrolidin-3-ylmethanol, as a yellow solid.

The compound was used without further characterization.

Intermediate 86 Methyl(1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 82, startingfrom methyl(1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 83) and 2-((S)-pyrrolidin-3-yl)propan-2-ol, as a yellowsolid.

The compound was used without further characterization.

Intermediate 87 Methyl(1aR,7bS)-5-[N-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl]benzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 82, startingfrom methyl(1aR,7bS)-5-{N-[4-fluoro-2-((Z)-3-methylsulfonyloxyprop-1-enyl)benzenesulfonyl]-N-(methoxycarbonyl)amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 83) and 2-((R)-pyrrolidin-3-yl)propan-2-ol, as a yellowsolid.

The compound was used without further characterization.

Intermediate 88 Methyl(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

4-Fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonyl chloride(Intermediate 89, 0.53 g) in DCM (10 mL) was added to a solution ofmethyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.243 g) in DCM (15 mL) and pyridine (2 mL) and themixture was stirred at room temperature for 21 hours. The volatiles wereremoved by evaporation and the residue was purified by chromatography onsilica, eluting with a mixture of 2M ammonia in methanol and DCM, with agradient of 0-20%, to give methyl(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.097 g) as a brown solid.

¹H NMR (CDCl₃) δ: 7.91 (1H, dd), 7.23 (1H, d), 7.07-6.99 (1H, m),6.99-6.93 (2H, m), 4.39-4.29 (2H, m), 3.83-3.72 (4H, m), 3.57-3.46 (2H,m), 3.13-3.00 (2H, m), 3.00-2.75 (2H, m), 2.61 (1H, td), 2.35-2.22 (1H,m), 2.22-2.074 (3H, m), 1.98-1.88 (1H, m), 1.87-1.67 (2H, m), 1.59-1.43(1H, m), 1.09-0.96 (2H, m).

Intermediate 894-Fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonyl chloride

2-(3-Fluorobenzyl)hexahydro-1H-pyrrolizine (Intermediate 90, 0.365 g) inDCE (3 mL) was added dropwise to a solution of chlorosulfonic acid (1mL) in DCE (3 mL) at −10° C. The mixture was stirred for 1 hour at −10°C. then allowed to warm to room temperature and stirred for 16 hours.The mixture was carefully added to ice and water containing sodiumbicarbonate (3.78 g) and then extracted with DCM. The organic layer wasdried (Na₂SO₄) and filtered and the filtrate was evaporated to dryness.

The compound was used without further characterization.

Intermediate 90 2-(3-Fluorobenzyl)hexahydro-1H-pyrrolizine

A mixture of 2-(3-fluorobenzylidene)hexahydro-1H-pyrrolizine (mixture ofE and Z isomers, Intermediate 91, 0.4 g), palladium hydroxide (20% oncarbon, 0.1 g), ethyl acetate (10 mL) and IMS (10 mL) was degassed bynitrogen/vacuum purging. The reaction mixture was stirred vigorouslyunder an atmosphere of hydrogen for 2 hours. The mixture was filteredand the filtrate was evaporated to dryness to give2-(3-fluorobenzyl)hexahydro-1H-pyrrolizine (0.365 g) as a brown oil.

¹H NMR (CDCl₃) δ: 7.29-7.18 (1H, m), 6.99-6.80 (3H, m), 3.89-3.77 (1H,m), 3.48-3.40 (1H, m), 3.23-3.12 (1H, m), 2.76-2.57 (4H, m), 2.30-2.10(2H, m), 2.04-1.85 (3H, m), 1.65-1.53 (1H, m), 1.23-1.09 (1H, m).

Intermediate 91 2-(3-Fluorobenzylidene)hexahydro-1H-pyrrolizine (mixtureof E and Z isomers)

Potassium tert-butoxide (1.31 g) was added to a solution of(3-fluorobenzyl)triphenylphosphonium bromide (Intermediate 52, 4.96 g)in dry THF (50 mL) at room temperature. The mixture was stirred for 20minutes, then a solution of tetrahydro-1H-pyrrolizin-2(3H)-one(Intermediate 92, 1.25 g) in dry THF (20 mL) was added. The mixture wasstirred for 20 hours then diluted with water and extracted with ethylacetate. The organic layer was dried (Na₂SO₄), filtered and the filtratewas evaporated to dryness. The residue was purified by chromatography onsilica, eluting with a mixture of 2M ammonia in methanol and DCM, with agradient of 0-10%, to give2-(3-fluorobenzylidene)hexahydro-1H-pyrrolizine as a mixture of E and Zisomers (0.4 g).

¹H NMR (CDCl₃) δ: 7.37-7.27 (1H, m), 7.07-6.80 (3H, m), 6.52-6.42 (1H,m), 4.29-3.89 (2H, m), 3.68-3.54 (1H, m), 3.52-3.40 (1H, m), 3.12-2.97(1H, m), 2.80-2.68 (1H, m), 2.61-2.48 (1H, m), 2.32-2.13 (1H, m),2.08-1.93 (2H, m), 1.75-1.60 (1H, m).

Intermediate 92 Tetrahydro-1H-pyrrolizin-2(3H)-one

Ethyl (1-ethoxycarbonylmethylpyrrolidin-2-yl)acetate (Intermediate 93, 5g) in xylene (30 mL) was added dropwise over 60 minutes to a suspensionof sodium hydride (60% oil dispersion, 0.863 g) in xylene (75 mL) andIMS (0.1 mL) at 60° C. The mixture was stirred and heated at 60° c. for1 hour, then, the temperature was raised to 75° C. and stirring wascontinued for 1.5 hours. After cooling, acetic acid (4.5 mL), water (15ml) and 2M hydrochloric acid (120 mL) were added. The aqueous layer wasseparated and heated at 110° C. for 2 hours. After cooling, the mixturewas concentrated in vacuo and the residue was dissolved in water,neutralized by addition of solid sodium carbonate and extracted withchloroform. The organic phase was dried (Na₂SO₄), filtered and thesolvent was removed in vacuo to give tetrahydro-1H-pyrrolizin-2(3H)-one(1.25 g).

LCMS (Method E) r/t 0.36 (M+H) 126.

Intermediate 93 Ethyl (1-ethoxycarbonylmethylpyrrolidin-2-yl)acetate

Ethyl bromoacetate (6.05 g) was added to a mixture of ethylpyrrolidin-2-ylacetate hydrochloride (Intermediate 94, 6.38 g) andpotassium carbonate (12.3 g) in IMS (150 mL) and the mixture was heatedat reflux for 4 hours. After cooling, the mixture was concentrated invacuo and the residue was partitioned between water and diethyl ether.The organic layer was dried (Na₂SO₄) and filtered and the filtrate wasevaporated to dryness to give ethyl(1-ethoxycarbonylmethylpyrrolidin-2-yl)acetate (5.0 g).

¹H NMR (CDCl₃) δ: 4.24-4.05 (4H, m), 3.53 (1H, d), 3.31-3.14 (2H, m),3.12-2.98 (1H, m), 2.64-2.44 (2H, m), 2.37-2.23 (1H, m), 2.15-1.98 (1H,m), 1.89-1.70 (2H, m), 1.66-1.52 (1H, m), 1.32-1.19 (6H, m).

Intermediate 94 Ethyl pyrrolidin-2-ylacetate hydrochloride

TFA (30 mL) was added slowly to a solution of ethyl6-(tert-butoxycarbonylamino)hex-2-enoate (Intermediate 95, 10.25 g) inDCM (100 mL) at 0° C. The solution was allowed to warm to roomtemperature and stirred for 24 hours. The mixture was concentrated invacuo and the residue was azeotroped with toluene and DCM. The residuewas dissolved in DCM (100 mL) and cooled to 0° C. Triethylamine (27 mL)was added and the mixture was allowed to warm to room temperature andstirred for 18 hours. The volatiles were removed in vacuo and theresidue was dissolved in diethyl ether (200 mL) and treated with 4M HClin dioxane (40 mL). The mixture was stirred for 30 minutes thenevaporated to dryness to give ethyl pyrrolidin-2-ylacetate hydrochloride(6.38 g).

¹H NMR (CDCl₃) δ: 9.72 (2H, br d), 4.18 (2H, q), 4.01-3.83 (1H, m),3.48-3.34 (2H, m), 3.26-3.14 (1H, m), 2.92-2.78 (1H, m), 2.38-2.20 (1H,m), 2.18-1.95 (2H, m), 1.85-1.67 (1H, m), 1.27 (3H, t).

Intermediate 95 Ethyl 6-(tert-butoxycarbonylamino)hex-2-enoate

DIBAL (1M in toluene, 56 mL) was added dropwise to a solution oftert-butyl 2-oxo-pyrrolidine-1-carboxylate (9.8 g) in dry THF (150 mL)at −70° C. under an atmosphere of nitrogen. The mixture was stirred for1.5 hours at −70° C., then a saturated solution of Rochelle's salt wasadded followed by ethyl acetate. The mixture was stirred until two clearlayers formed, then the organic layer was dried (Na₂SO₄) and filtered.The filtrate was evaporated to dryness and the residue was dissolved indry toluene (200 mL) and treated with(carbethoxymethylene)triphenylphosphorane (19.54 g). The resultantmixture was heated at reflux under an atmosphere of nitrogen for 18hours. After cooling, the mixture was concentrated in vacuo and theresidue was purified by chromatography on silica, eluting with a mixtureof ethyl acetate and cyclohexane, with a gradient of 0-35%, to giveethyl 6-(tert-butoxycarbonylamino)hex-2-enoate (10.25 g) as a yellowoil.

¹H NMR (CDCl₃) δ: 6.94 (1H, dt), 5.83 (1H, dt), 4.53 (1H, br s), 4.18(2H, q), 3.20-3.07 (2H, m), 2.29-2.18 (2H, m), 1.72-1.61 (2H, m), 1.44(9H, s), 1.28 (3H, t).

Intermediate 96 Methyl(1aR,7bS)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Triethylamine (2.4 mL) was added to a mixture of5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenylaceticacid (Intermediate 97, 0.740 g), (R)-1-ethylpyrrolidin-3-ylaminedihydrodhloride salt (Intermediate 100, 0.48 g) and EDAC (0.65 g) in DCM(20 mL) at room temperature under an atmosphere of nitrogen. The mixturewas stirred at room temperature for 16 hours then diluted with DCM andwashed with water. The aqueous phase was extracted with further DCM andthe combined organic layers were dried (Na₂SO₄) and filtered. Thefiltrate was concentrated in vacuo and the residue was combined with thecrude material obtained from a second reaction using5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenylaceticacid (Intermediate 97, 0.1 g) under the same conditions described above.The combined crude products were purified by chromatography on silica,eluting with a mixture of methanol and DCM, with a gradient of 0-20%, togive (0.740 g) as a white solid.

LCMS (Method A) r/t 2.29 (M+H) 532.

Intermediate 975-Fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)phenylaceticacid

1M Sodium hydroxide solution (5.2 mL) was added to a solution of methyl(1aR,7bS)-5-[4-fluoro-2-(methoxycarbonylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(Intermediate 98, 1.52 g) in methanol (25 mL) and the mixture wasstirred and heated at 50° C. for 2 hours. Further 1M sodium hydroxidesolution (5.0 mL) was added and stirring was continued for 2 hours at50° C. After cooling, the mixture was evaporated to dryness and theresidue was dissolved in ethyl acetate and water and acidified withconcentrated hydrochloric acid. The organic layer was dried (Na₂SO₄) andfiltered and the filtrate was concentrated in vacuo to give5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenylaceticacid (1.51 g) as a white gum.

¹H NMR (CDCl₃): 8.83 (1H, br, s), 7.86 (1H, dd), 7.22 (1H, d), 7.08-6.96(3H, m), 4.32 (1H, d), 4.00 (2H, d), 3.76 (1H, dd), 3.73 (3H, s),1.98-1.87 (1H, m), 1.77-1.67 (1H, m), 1.06-0.99 (2H, m).

Intermediate 98 Methyl(1aR,7bS)-5-[4-fluoro-2-(methoxycarbonylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Pyridine (6 mL) was added to a stirred mixture of methyl2-chlorosulfonyl-5-fluorophenylacetate (Intermediate 99, 1.32 g) andmethyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A 1.09 g) in DCM (20 mL) at 0° C. under an atmosphere ofnitrogen. The mixture was allowed to warm slowly to room temperature andstirred for 1 hour. The volatiles were removed by evaporation and theresidue was partitioned between DCM and 1M hydrochloric acid. Theaqueous phase was extracted with DCM and the combined organic layerswere dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuoand the residue was purified by chromatography on silica, eluting with amixture of ethyl acetate and cyclohexane, with a gradient of 0-50%, togive methyl(1aR,7bS)-5-[4-fluoro-2-(methoxycarbonylmethyl)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(1.57 g) as a gum.

¹H NMR (CDCl₃) δ: 8.77 (1H, br, s), 7.84 (1H, dd), 7.22 (1H, d),7.09-6.94 (3H, m), 4.33 (1H, d), 4.01 (2H, s), 3.79 (1H, d), 3.76 (3H,s), 3.69 (3H, s), 1.99-1.89 (1H, m), 1.80-1.68 (1H, m), 1.08-0.98 (2H,m).

Intermediate 99 Methyl 2-chlorosulfonyl-5-fluorophenylacetate

Methyl 3-fluorophenylacetate (1.51 g) was added dropwise tochlorosulphonic acid (7 mL) with stirring and ice cooling. The coolingbath was removed and the mixture was allowed to warm to room temperatureand left to stand for 16 hours. The mixture was added to a mixture ofice and ethyl acetate and the organic layer was separated, washed withwater, dried (MgSO₄) and filtered. The filtrate was concentrated invacuo and the residue was purified by chromatography on silica, elutingwith a mixture of ethyl acetate and cyclohexane, with a gradient of0-20%, to give methyl 2-chlorosulfonyl-5-fluorophenylacetate (1.42 g) asa white solid.

¹H NMR (CDCl₃) δ: 8.16 (1H, dd), 7.29-7.16 (2H, m), 4.19 (2H, s), 3.76(3H, s).

Intermediate 100 (R)-1-Ethylpyrrolidin-3-amine dihydrochloride salt

A solution of tert-butyl (R)-1-ethylpyrrolidin-3-ylcarbamate(Intermediate 101, 0.215 g) in methanol (1 mL) was treated with 4M HClin dioxane (4 mL) and the mixture was stirred at room temperature for 30minutes. The volatiles were removed by evaporation to give(R)-1-ethylpyrrolidin-3-amine dihydrochloride salt (0.188 g) as a whitegum.

The compound was used without further characterization.

Intermediate 101 tert-Butyl (R)-1-ethylpyrrolidin-3-ylcarbamate

A mixture of tert butyl (R)-pyrrolidin-3-ylcarbamate (5.18 g),bromoethane (2.2 mL) and potassium carbonate (7.68 g) in acetonitrile(100 mL) was stirred at room temperature for 16 hours. Additionalbromoethane (0.3 mL) was added and stirring was continued for 2 hours.The volatiles were removed by evaporation and the residue waspartitioned between DCM and water. The aqueous phase was extracted withDCM and the combined organic layers were dried (Na₂SO₄) and filtered.The filtrate was concentrated in vacuo and the residue was purified bychromatography on silica, eluting with a mixture of 2M ammonia inmethanol and DCM, with a gradient of 0-10%, to give tert-butyl(R)-1-ethylpyrrolidin-3-ylcarbamate (3.62 g) as a colourless oil.

¹H NMR (CDCl₃): 4.93 (1H, br, s), 4.16 (1H, br, s), 2.85-2.75 (1H, m),2.59-2.53 (2H, br, m), 2.50-2.42 (2H, m), 2.32-2.19 (2H, m), 1.64-1.50(1H, m), 1.43 (9H, s), 1.10 (3H, t).

Intermediate 102 Methyl(1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A suspension of methyl(1aR,7bS)-5-[2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 103, 0.17 g) in DCM (5 mL) and methanol (2-3 drops) wastreated with sodium triacetoxyborohydride (0.2 g) followed byacetaldehyde (0.05 mL). The mixture was stirred at room temperature for1 hour then poured into water. The organic layers was dried (Na₂SO₄) andfiltered and the filtrate was concentrated in vacuo. The residue wascombined with material from a second reaction starting from methyl(1aR,7bS)-5-[2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.05 g) under the reaction conditions described above. The combinedresidues were purified by chromatography on silica, eluting with amixture of methanol and DCM, with a gradient of 0-100%, to give methyl(1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.12 g).

LCMS (Method A) r/t 2.20 and 2.33 (M+H) 471.

Intermediate 103 Methyl(1aR,7bS)-5-[2-((R)-pyrrolidin-3-ylmethyl)benzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Prepared by proceeding in a similar manner to Intermediate 78, startingfrom tert-butyl(R)-3-[2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyl]pyrrolidine-1-carboxylate(Intermediate 104), as a glass.

LCMS (Method E) r/t 2.15 and 2.26 (M+H) 443.

Intermediate 104 tert-Butyl(R)-3-[2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyl]pyrrolidine-1-carboxylate

n-Butyllithium (2.5M in hexanes, 0.75 mL) was added dropwise to a cooledsolution of tert-butyl (R)-3-(2-bromobenzyl)pyrrolidine-1-carboxylate(Intermediate 105, 0.6 g) in anhydrous THF (10 mL) under an atmosphereof argon at −78° C. Stirring was continued at −70° C. for 30 minutesthen sulfur dioxide was bubbled through the solution for 10 minutes at−78° C. The mixture was stirred at −78° C. for 30 minutes and thenallowed to warm slowly to room temperature. The volatiles were removedby evaporation and the residue was dissolved in DCM (20 mL) and cooledto 0° C. The mixture was treated with sulfuryl chloride (0.044 mL) andallowed to warm slowly to room temperature. Stirring was continued for30 minutes and then the mixture was evaporated to dryness. The residuewas dissolved in DCM (10 mL) and pyridine (5 mL) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.26 g) were added. The mixture was stirred at roomtemperature for 2.5 hours and then the volatiles were removed byevaporation. The residue was partitioned between DCM and water and theaqueous phase was extracted with DCM. The combined organic layers weredried (MgSO₄) and filtered and the filtrate was concentrated in vacuo.The reaction was repeated twice using tert-butyl(R)-3-(2-bromobenzyl)pyrrolidine-1-carboxylate (0.598 g and 0.252 grespectively) under the reaction conditions described above. Theresidues from the three reactions were combined and purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 0-30% to give tert-butyl(R)-3-[2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-5-ylsulfamoyl)benzyl]-pyrrolidine-1-carboxylate(0.23 g) as a glass.

¹H NMR (CDCl₃) δ: 8.99 (1H, d), 7.88 (1H, d), 7.49-7.38 (1H, m),7.30-7.18 (2H, m), 7.07-6.99 (1H, m), 4.31 (1H, d), 3.80-3.70 (4H, m),3.53-3.36 (2H, m), 3.26-3.14 (1H, m), 3.11-2.92 (2H, m), 2.91-2.73 (1H,m), 2.58-2.43 (1H, m), 1.98-1.82 (2H, m), 1.74-1.54 (2H, m), 1.44 (9H,s), 1.05-0.95 (2H, m).

Intermediate 105 tert-Butyl(R)-3-(2-bromobenzyl)pyrrolidine-1-carboxylate

Prepared by proceeding in a similar manner to Intermediate 25, startingfrom tert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (Intermediate26) and 2-bromobenzeneboronic acid as an oil.

¹H NMR (CDCl₃) δ: 7.54 (1H, t), 7.25-7.15 (2H, m), 7.12-7.03 (1H, m),3.59-3.38 (2H, m), 3.34-3.16 (1H, m), 3.09-2.98 (1H, m), 2.89-2.73 (2H,m), 2.60-2.47 (1H, m), 1.98-1.84 (1H, m), 1.68-1.56 (1H, m), 1.45 (9H,s).

Intermediate 106 Methyl(1aR,7bS)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of (S)-1-ethylpyrrolidine-3-carboxylic acid (Intermediate111, 0.089 g) and HOBT (0.084 g) in DCM (10 mL) was treated with EDAC(0.114 g) and the mixture was stirred for 10 minutes. Methyl(1aR,7bS)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 107, 0.25 g) was then added and stirring was continued atroom temperature for 3 days. The mixture was washed with water and theorganic layer was dried (Na₂SO₄) and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by chromatography onsilica, eluting with a mixture of 2M ammonia in methanol and DCM, with agradient of 0-15%, to give methyl(1aR,7bS)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.207 g) as a white solid.

LCMS (Method E) r/t 2.27 (M+H) 532.

Intermediate 107 Methyl(1aR,7bS)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

A solution of potassium carbonate (1.61 g) in water (10 mL) was added toa solution of methyl(1aR,7bS)-5-[4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 108, 1.17 g) in methanol (40 mL) and the resultant mixturewas stirred and heated at 45° C. for 2 hours. After cooling, the mixturewas concentrated in vacuo and the residue was partitioned between waterand DCM. The organic layer was washed with brine, dried (Na₂SO₄) andfiltered. The filtrate was concentrated in vacuo to give methyl(1aR,7bS)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(0.767 g) as a white solid.

LCMS (Method E) r/t 2.05 (M+H) 407.

Intermediate 108 Methyl(1aR,7bS)-5-[4-fluoro-2-(trifluoroacetylaminomethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate

Methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.972 g) was added to a solution of4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride(Intermediate 109, 1.53 g) in DCM (25 mL) and pyridine (6 mL). Themixture was stirred at room temperature for 18 hours. The volatiles wereremoved by evaporation and the residue was purified by chromatography onsilica, eluting with a mixture of ethyl acetate and cyclohexane, with agradient of 0-40%, to give methyl(1aR,7bS)-5-[4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(1.17 g) as a white solid.

LCMS (Method E) r/t 3.70 (M−H) 501.

Intermediate 109 4-Fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonylchloride

3-Fluoro-N-trifluoroacetylbenzylamine (Intermediate 110, 1.11 g) wasadded portionwise to chlorosulfonic acid (5 mL), while stirring andcooling in an ice bath. On completion of the addition, the ice bath wasremoved and the mixture was allowed to warm to room temperature thenheated at 70° C. for 3 hours. After cooling, the mixture was addedslowly to ice and the resultant suspension was extracted with ethylacetate, washed with water, dried (MgSO₄) and filtered. The filtrate wasevaporated to dryness to give4-fluoro-2-(trifluoroacetylaminomethyl)benzenesulfonyl chloride (1.53 g)as a brown solid.

¹H NMR (CDCl₃): 8.18 (1H, dd), 7.47 (1H, dd), 7.31-7.21 (1H, m), 7.18(1H, br s), 4.92 (2H, d).

Intermediate 110 3-Fluoro-N-trifluoroacetylbenzylamine

Trifluoroacetic anhydride (5.05 g) was added dropwise to an ice-cooledsolution of 3-fluorobenzylamine (2.5 g) and triethylamine (2.22 g) inethyl acetate (75 mL) while maintaining the temperature below 10° C. Themixture was stirred at 0-5° C. for 1 hour then allowed to warm to roomtemperature and stirred for 2 hours. Water was added and the layers wereseparated. The organic layer was washed with water, dried (MgSO₄) andfiltered. The filtrate was evaporated to dryness to give3-fluoro-N-trifluoroacetylbenzylamine (4.58 g) as an oil whichcrystallised on standing to a white solid.

¹H NMR (CDCl₃): 7.41-7.27 (1H, m), 7.13-6.92 (3H, m), 6.72 (1H, br s),4.53 (2H, d).

Intermediate 111 (S)-1-Ethylpyrrolidine-3-carboxylic acid

A mixture of benzyl (S)-1-ethylpyrrolidine-3-carboxylate (Intermediate112, 0.563 g), 20% palladium hydroxide on carbon (0.056 g), ethylacetate (9 mL) and IMS (1 mL) was degassed and stirred under anatmosphere of hydrogen for 4 hours. The mixture was filtered throughCelite, washing the pad with ethyl acetate and the filtrate wasconcentrated in vacuo to give (S)-1-ethylpyrrolidine-3-carboxylic acid(0.318 g) as a solid.

¹H NMR (CDCl₃) δ: 12.46-10.55 (1H, br s), 3.84-3.57 (1H, br s),3.49-3.26 (1H, br s), 3.26-2.93 (5H, m), 2.50-2.33 (1H, m), 2.28-2.11(1H, m), 1.35 (3H, t).

Intermediate 112 Benzyl (S)-1-ethylpyrrolidine-3-carboxylate

Ethyl bromide (0.785 mL) was added to a mixture of benzyl(S)-pyrrolidine-3-carboxylate hydrochloride salt (Intermediate 113, 2.53g) and potassium carbonate (3.62 g) in DMF (50 mL) at room temperatureand the mixture was stirred for 3 days. The mixture was diluted withwater and extracted with diethyl ether. The organic layer was washedwith brine, dried (Na₂SO₄) and filtered. The filtrate was concentratedin vacuo and the residue was dissolved in cyclohexane and filteredthrough a PTFE membrane. The filtrate was concentrated in vacuo and theresidue was purified by chromatography on silica, eluting with a mixtureof methanol and ethyl acetate, with a gradient of 0-10%, to give benzyl(S)-1-ethylpyrrolidine-3-carboxylate (1.06 g).

LCMS (Method E) r/t 1.50 (M+H) 234.

Intermediate 113 Benzyl (S)-pyrrolidine-3-carboxylate hydrochloride salt

A solution of 3-benzyl 1-tert-butyl (S)-pyrrolidine-1,3-dicarboxylate(Intermediate 114, 3.2 g) in DCM (25 mL) was treated with HCl (4M indioxane) and the mixture was stirred at room temperature for 18 hours.The volatiles were removed by evaporation to give benzyl(S)-pyrrolidine-3-carboxylate hydrochloride salt as a sticky solid.

LCMS (Method E) r/t 1.46 (M) 206.

Intermediate 114 3-Benzyl 1-tert-butyl (S)-pyrrolidine-1,3-dicarboxylate

DBU (0.764 mL) was added to a mixture of benzyl bromide (0.61 mL),(S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (1 g) inanhydrous toluene (10 mL) and the mixture was stirred at roomtemperature for 24 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography onsilica, eluting with a mixture of ethyl acetate and cyclohexane, with agradient of 0-35%, to give 3-benzyl 1-tert-butyl(S)-pyrrolidine-1,3-dicarboxylate (0.859 g).

¹H NMR (CDCl₃) δ: 7.39-7.29 (5H, m), 5.14 (2H, s), 3.70-3.41 (3H, m),3.41-3.27 (1H, m), 3.08 (1H, m), 2.13 (2H, q), 1.45 (9H, s).

Intermediate 115 Methyl(1aR,7bS)-5-(2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoro-acetylamino]ethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate

Pyridine (1 mL) was added to a stirred, cooled solution of2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonylchloride (Intermediate 116, 0.433 g) and methyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.22 g) in DCM (10 mL) at 0° C. The mixture wasallowed to warm to room temperature and stirred for 2.5 hours. Furthermethyl(1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate(Intermediate 8A, 0.08 g) was added and stirring was continued for 1hour. The mixture was partitioned between saturated aqueous sodiumbicarbonate and DCM and the aqueous layer was extracted with furtherDCM. The combined organic layers were dried (Na₂SO₄) and filtered. Thefiltrate was evaporated to dryness and the residue was purified bychromatography on silica, eluting with a mixture of methanol and ethylacetate, with a gradient of 0-20% to give methyl(1aR,7bS)-5-(2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoro-acetylamino]ethyl}-4-fluorobenzene-sulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate(0.048 g) as a gum.

LCMS (Method A) r/t 2.63 (M+H) 614.

Intermediate 1162-{2-[N—((R)-1-Ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonylchloride

Chlorosulfonic acid (1.1 mL) was added slowly to a cooled solution of1-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-3-fluorobenzene(Intermediate 117, 0.54 g) in DCM (2 mL) in an ice bath. On completionof the addition, the mixture was allowed to warm slowly to roomtemperature and stirred for 30 minutes. The mixture was poured into iceand extracted with DCM, dried (Na₂SO₄) and filtered. The filtrate wasevaporated to dryness to give2-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-4-fluorobenzenesulfonylchloride (0.048 g) as a white solid.

LCMS (Method B) r/t 2.32 (M+H) 431.

Intermediate 1171-{2-[N—((R)-1-Ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-3-fluorobenzene

Trifluoroacetic anhydride (0.43 mL) was added to a cooled solution of((R)-1-ethylpyrrolidin-3-yl)-[2-(3-fluorophenyl)ethyl]amine(Intermediate 118, 0.58 g) and triethylamine (1.03 mL) in DCM (20 mL) inan ice bath. On completion of the addition the mixture was allowed towarm to room temperature and stirred for 2 hours. Furthertrifluoroacetic anhydride (0.1 mL) was added and stirring was continuedfor 30 minutes. The mixture was partitioned between saturated aqueoussodium bicarbonate and DCM and the aqueous layer was extracted with DCM.The combined organic layers were dried (Na₂SO₄) and filtered. Thefiltrate was evaporated to dryness and the residue was purified bychromatography on silica, eluting with a mixture of methanol and DCMwith a gradient of 0-10%, to give1-{2-[N—((R)-1-ethylpyrrolidin-3-yl)-N-trifluoroacetylamino]ethyl}-3-fluorobenzene(0.55 g) as a gum.

¹H NMR (CDCl₃) δ: 7.32-7.21 (1H, m), 7.06-6.87 (3H, m), 4.69-4.49 (1H,m), 3.68 (2H, t), 3007-2.82 (3H, m), 2.72-2.63 (1H, m), 2.58-2.32 (3H,m), 2.28-2.14 (2H, m), 1.81-1.67 (1H, m), 1.10 (3H, t).

Intermediate 118((R)-1-Ethylpyrrolidin-3-yl)-[2-(3-fluorophenyl)ethyl]amine

A mixture of 1-methanesulfonyloxy-2-(3-fluorophenyl)ethane (Intermediate119, 0.74 g), (R)-1-ethylpyrrolidin-3-amine dihydrochloride salt(Intermediate 100, 0.64 g) and potassium carbonate (2.36 g) inacetonitrile (15 mL) was stirred and heated in a sealed vial at 80° C.overnight. The reaction was repeated twice, using1-methanesulfonyloxy-2-(3-fluorophenyl)ethane (Intermediate 119, 0.74 gand 0.31 g respectively) under the reaction conditions described above.The combined crude reaction mixtures were partitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetateand the combined organic layers were dried (Na₂SO₄) and filtered. Thefiltrate was evaporated to dryness and the residue was purified bychromatography on silica, eluting with a mixture of 2M ammonia inmethanol and DCM with a gradient of 0-20%, to give((R)-1-ethylpyrrolidin-3-yl)-[2-(3-fluorophenyl)ethyl]amine (0.59 g) asa gum.

¹H NMR (CDCl₃) δ: 7.28-7.20 (1H, m), 7.01-6.85 (3H, m), 3.36-3.27 (1H,m), 2.88-2.75 (4H, m), 2.75-2.68 (1H, m), 2.64-2.55 (1H, m), 2.53-2.2.39(3H, m), 2.36-2.29 (1H, m), 2.18-2.06 (1H, m), 1.57-1.46 (1H, m), 1.09(3H, t).

Intermediate 119 1-Methanesulfonyloxy-2-(3-fluorophenyl)ethane

Methanesulfonyl chloride (0.92 mL) was added to a stirred, cooledsolution of 2-(3-fluorophenyl)ethanol (1.28 g) and triethylamine (2 mL)in DCM (15 mL) at 0° C. under an atmosphere of nitrogen. On completionof the addition, the mixture was stirred at 0° C. for 30 minutes then atroom temperature for 1.5 hours. The mixture was partitioned between DCMand 1M hydrochloric acid and the aqueous layer was extracted with DCM.The combined organic layers were dried (Na₂SO₄) and filtered. Thefiltrate was evaporated to dryness and the residue was purified bychromatography on silica, eluting with a mixture of ethyl acetate andcyclohexane, with a gradient of 0-100% to give1-methanesulfonyloxy-2-(3-fluorophenyl)ethane (1.92 g) as a colourlessoil.

¹H NMR (CDCl₃) δ: 7.33-7.26 (1H, m), 7.05-6.92 (3H, m), 4.42 (2H, t),3.06 (2H, t), 2.89 (3H, s).

Biological Example

Compounds are tested for their capacity to inhibit recombinant humanMetAP2 activity using the following assay.

Human recombinant MetAP2 expressed in Sf9 cells followed by affinitypurification and EDTA treatment to remove endogenous active site cationwas dialysed against MnCl₂ to produce the manganese enzyme used in theassay. The assay was carried out for 30 minutes at 25° C. in 50 mM HEPESbuffer containing 100 mM NaCl, pH 7.5 the presence of 0.75 mMMethionine-Alanine-Serine (MAS) substrate and 50 μg/ml amino acidoxidase using a dilution of purified MetAP2 giving >3-fold signal:noise.Cleavage of the substrate by MetAP2 and oxidation of free methionine byamino acid oxidase was detected and quantified using fluorescencegenerated by Amplex red (10-acetyl-3,7-dihydroxyphenoxazine) incombination with horseradish peroxidase which detects H₂O₂ releasedduring the oxidation step. The fluorescent signal was detected using amultiwell fluorimeter. Compounds were diluted in DMSO prior to additionto assay buffer, the final DMSO concentration in the assay being 1%.

The IC₅₀ is defined as the concentration at which a given compoundachieves 50% inhibition of control. IC₅₀ values are calculated using theXLfit software package (version 2.0.5).

Compounds of the invention demonstrated activity in the assay of thisExample as indicated in the following table, wherein A represents <0.05μM, B represents IC₅₀ between 0.05 μM and 0.5 μM, and C represents IC₅₀>0.504.

Ac- Compound name tivity(1aR,7bS)-5-[2-(2-Diethylaminomethylcyclopropyl)-4-fluoro- Bbenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid First eluting enantiomer of(1aR,7bS)-5-[2-(2-diethylamino- Amethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid Second elutingenantiomer of (1aR,7bS)-5-[2-(2-diethylamino- Bmethylcyclopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-{4-Fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]- Bbenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-(3-Diethylamino-2,2-dimethylpropyl)-4- Afluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro-[c]chromene-4-carboxylic acid(1aR,7bS)-5-[4-Fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene- Asulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylicacid (1aR,7bS)-5-[4-Fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene- Asulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylicacid (1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)- Apyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro- Abenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-((Z)-1-Azabicyclo[2.2.2]oct-3-ylidenemethyl)-4- Afluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-((E)-1-Azabicyclo[2.2.2]oct-3-ylidenemethyl)-4- Afluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-{2-[(E)-(1-Ethylpiperidin-3-ylidene)methyl]-4- Afluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-{2-[(Z)-(1-Ethylpiperidin-3-ylidene)methyl]-4- Bfluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid First eluting enantiomer of(1aR,7bS)-5-[2-(1-ethylpiperidin-3- Aylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid Second eluting enantiomer of(1aR,7bS)-5-[2-(1-ethylpiperidin-3- Aylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-{2-[2-((S)-1-Ethylpyrrolidin-2-yl)ethyl]-4-fluoro- Abenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-{4-Fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3- Aylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-((Endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3- Ayl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-((Exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3- Ayl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin- A1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5{4-Fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1- Benyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1- Byl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-(3-Ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro- Bbenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-{4-Fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]- Abenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((S)-3-hydroxymethylpyrrolidin- A1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-{4-Fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin- A1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2- Ayl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-(4-Fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2- Ayl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-[4-Fluoro-2-(hexahydro-1H-pyrrolizin-2- Aylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-{2-[((S)-1-Ethylpyrrolidin-3-ylcarbamoyl)methyl]- A4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid(1aR,7bS)-5-[2-((3R)-1-Ethylpyrrolidin-3-ylmethyl)benzene- Asulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylicacid (1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino- Amethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid - formic acid (1:1)(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4- Afluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid - formic acid (1:1)

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted below, are hereby incorporated by reference in their entirety forall purposes as if each individual publication or patent wasspecifically and individually incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention.

What is claimed is:
 1. A compound selected from the group consisting of:(1aR,7bS)-5-[2-(2-diethylaminomethylcyclopropyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid, or enantiomers thereof;(1aR,7bS)-5-{4-fluoro-2-[2-(pyrrolidin-1-ylmethyl)cyclopropyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-(3-diethylamino-2,2-dimethylpropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopro-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[4-fluoro-2-((R)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[4-fluoro-2-((S)-pyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((Z)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((E)-1-azabicyclo[2.2.2]oct-3-ylidenemethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[(E)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[(Z)-(1-ethylpiperidin-3-ylidene)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid, or enantiomers thereof;(1aR,7bS)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(R)-1-(2-hydroxyethyl)pyrrolidin-3-ylmethyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-((exo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl)methyl-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(3-hydroxy-3-methylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5{4-fluoro-2-[(Z)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-(4-hydroxy-4-methylpiperidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-(3-ethyl-3-azabicyclo[3.1.0]hex-6-yl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-2-((S)-pyrrolidin-2-yl)ethenyl]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; (1)enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{4-fluoro-2-[(Z)-3-((R)-3-hydroxymethylpyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(S)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-(4-fluoro-2-{(Z)-3-[(R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]prop-1-enyl}benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[4-fluoro-2-(hexahydro-1H-pyrrolizin-2-ylmethyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((3R)-1-ethylpyrrolidin-3-ylmethyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[((S)-1-ethylpyrrolidine-3-carbonyl)amino-methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid-formic acid (1:1);(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid-formic acid (1:1) and pharmaceutically acceptable salts,stereoisomers, esters and prodrugs thereof.
 2. A pharmaceuticallyacceptable composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 3. A method of treating and/orcontrolling obesity, comprising administering to a patient in needthereof an effective amount of a compound of claim
 1. 4. A method ofinducing weight loss in a patient in need thereof, comprisingadministering to said patient an effective amount of a compound ofclaim
 1. 5. The method of claim 3, wherein the patient is a human. 6.The method of claim 3, wherein the patient is a cat or dog.
 7. Themethod of claim 3, wherein the patient has a body mass index greaterthan or equal to about 30 kg/m² before the administration.
 8. The methodof claim 3, wherein the compound is administered orally.
 9. Thecomposition of claim 2, wherein the composition is formulated as a unitdose.
 10. The composition of claim 2, wherein the composition isformulated for oral administration.
 11. The composition of claim 2,wherein the composition is formulated for intravenous or subcutaneousadministration.
 12. The method of claim 3, comprising administering saidcompound in an amount sufficient to establish inhibition ofintracellular MetAP2 effective to increase thioredoxin production in thepatient and to induce multi organ stimulation of anti-obesity processesin the subject.
 13. The method of claim 12, comprising administeringsaid compound in an amount insufficient to reduce angiogenesis in thepatient.